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Article information

Abstract

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 is a protein that in humans is encoded by the MALT1 gene.[1][2][3] It's the human paracaspase.


Function

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Structure of the MALT1 protein (PDB: 2G7R​)

Genetic ablation of the paracaspase gene Malt1 in mice and biochemical studies have shown that MALT1 is a crucial protein for T and B lymphocytes activation. It has an important role in the activation of the transcription factor NF-κB, in the production of interleukin-2 (IL-2) and in T and B lymphocytes proliferation[4][5] MALT1 plays a critical role in the adaptive immunity also in humans, and patients deficient for MALT1 show combined immunodeficiency (CID), failure to thrive, osteoprorosis and atopic dermatitis. [6][7][8] The osteoporosis and atopic dermatitis phenotypes have also been replicated in Malt1 knock out mice.[9][10] Conditional Malt1 mouse models show that the osteoporosis phenotype is dependent on MALT1 in T cells. On the other hand, it is still unknown what cell type is responsible for the atopic dermatitis phenotype (T cells and keratinocytes are excluded).

In addition, a role for MALT1 has been shown in the innate immune response mediated by the zymosan receptor Dectin-1 in macrophages and dendritic cells, and in response to the stimulation of certain G protein-coupled receptors.[11] At this moment, most functional analyses of MALT1 have been performed in lymphocytes (T cells and B cell lymphomas). The role of MALT1 in other cell types and signaling pathways are much less understood.

Sequence analysis show that MALT1 has an N-terminal death domain, two central immunoglobulin-like domains involved in the binding to the B-cell lymphoma 10 (BCL10) protein and a caspase-like (paracaspase) domain. Two alternatively spliced transcript variants encoding different isoforms have been described for this gene.[12] The death domain and immunoglobulin-like domains participate in binding to BCL10. Activation of MALT1 downstream NF-κB signaling and protease activity occurs when BCL10/MALT1 gets recruited to an activated CARD-CC family protein (CARD9, -10, -11 or -14) in a so-called CBM (CARD-CC/BCL10/MALT1) signaling complex.

MALT1, being a paracaspase, has been shown to have proteolytic activity through its caspase-like domain in T lymphocytes and other cell types. Cysteine 464 and histidine 415 are crucial for this activity. Like metacaspases, the paracaspase cleaves substrates after an arginine residue. To date, several MALT1 protease substrates have been described (see below). The role of specific substrate cleavage events are unclear, but the MALT1 protease activity plays a critical role in the regulation of the immune system.

"Protease dead" knock-in mice where the MALT1 catalytic cysteine has been mutated to an alanine show lethal autoimmunity, [13][14][15] and conditional mutant mice have shown that this MALT1 protease-dependent immune regulation is taking place in T cells,[16] and especially in regulatory T cells.[17][18] The lethal autoimmunity is driven by IFNγ-producing T cells.[13] Until now, no uncleavable knock-in substrate mutant mouse has replicated this phenotype, which means that it is unclear how MALT1 protease activity is regulating immune homeostasis.[19] Interestingly, it seems like MALT1 protease inhibition in adult animals leads to a less severe autoimmunity,[20][21] which might indicate that thymic regulatory T cells, which develop at an early age, are important for the suppression of autoimmunity. This is also encouraging for the potential therapeutic use of MALT1 protease inhibitors:

By targeting MALT1 proteolytic activity, it might be possible to develop new drugs that might be useful for the treatment of certain lymphomas, solid tumors or autoimmune disorders. Not only by affecting the cancer cells themselves, but also to enhance immune check point inhibition by suppressing regulatory T cells, enhance cancer cell killing by promoting IFNγ-producing T cells, and possibly also influence the polarization of tumor-associated macrophages towards a more pro-inflammatory phenotype. [22]

Interactions

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MALT1 has been shown to interact with BCL10,[23] TRAF6 and SQSTM1/p62. The scaffold activity of MALT1 binding TRAF6 is critical for NF-κB activation downstream of CBM complex formation. In addition to NF-κB activation is MALT1 also important for mTOR activation in T cells and keratinocytes.[24][25]

Protease substrates

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MALT1 (PCASP1) is part of the paracaspase family and shows proteolytic activity. Since many of the substrates are involved in regulation of inflammatory responses, the protease activity of MALT1 has emerged as an interesting therapeutic target. The general pattern of MALT1 substrate specificity is a hydrophobic amino acid at P4 and small uncharged residues surrounding the substrate arginine (P1 and P1'). There are however exceptions to this rule. For example, the tetrapeptide GASR is a poor substrate,[26] and for A20 it has been shown that the P5 leucine (LGASR) is required for A20 cleavage.[27] Currently known protease substrates are (in order of reported discovery):

MALT1 protease substrates
Substrate Reference Cleavage sequence
A20 (TNFAIP3) [28] LGASR/G
BCL10 [29] LRSR/T
CYLD [30] FMSR/G
RELB [31] LVSR/G
regnase-1/MCPIP1 (ZC3H12A) [32] LVPR/G
Roquin-1(RC3H1) [33] LIPR/G
Roquin-2(RC3H2) [33] LISR/S
MALT1 auto-proteolysis [34] LCCR/A
MALT1 auto-proteolysis [35] HCSR/T
HOIL1 (RBCK1) [36][37][38] LQPR/G
N4BP1 [39] FVSR/G
CARD10 [40] LRCR/G
ZC3H12D [41] LVPR/G
ZC3H12B [41] LVPR/G
TAB3 [41] LQSR/G
CASP10 [41] LVSR/G
CILK1 [41] LISR/S
ILDR2 [41] GASR/G LVSR/T GASR/G
TANK [41] HIPR/V

Specifically by the oncogenic IAP2-MALT1 fusion:

Protease inhibitors

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Since MALT1 protease activity is a promising therapeutic target. Different screenings have been performed which have resulted in several types of protease inhibitors.[44] There is active competition between multiple pharma companies and independent research groups in drug development against the MALT1 protease activity.[45]

Active site inhibitors

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  • Substrate peptide-based active-site inhibitor: Initially described with the metacaspase inhibitor VRPR-fmk.[29] Others have developed peptide inhibitors based on the optimal peptide sequence (LVSR) or further chemical modifications.
  • Janssen Pharmaceutica is currently performing a clinical trial with this class of inhibitors.[46][47]
  • A molecular modeling approach led to the development of the small molecule active site inhibitor MI-2.[48]

Allosteric inhibitors

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Natural products

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Unknown

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  • VIB is developing MALT1 protease inhibitors in collaboration with the Leuven-based spin-off Centre for Drug Design and Discovery (CD3) [55][61]
  • Chordia therapeutics is entering a clinical trial with a MALT1 protease inhibitor in 2020 [62]
  • Monopteros has a MALT1 inhibitor against solid tumor cancer. [63]
  • Shrödinger has a compound in phase 1 clinical trials against mantle cell lymphoma. [64]
  • Exelixis has a "CARD11-BCL10-MALT1" complex inhibitor in phase 1 clinical trial. [65]
  • Rheos medicines has a clinical trial of their compound against autoimmune disease. [66]

References

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  1. ↑ Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P (June 1999). "The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas". Blood 93 (11): 3601–9. doi:10.1182/blood.V93.11.3601. PMID 10339464. 
  2. ↑ Hosaka S, Akamatsu T, Nakamura S, Kaneko T, Kitano K, Kiyosawa K, Ota H, Hosaka N, Miyabayashi H, Katsuyama T (July 1999). "Mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum with chromosomal translocation of the t(11;18)(q21;q21) and an additional aberration of trisomy 3". Am J Gastroenterol 94 (7): 1951–4. doi:10.1111/j.1572-0241.1999.01237.x. PMID 10406266. 
  3. ↑ Akagi T, Motegi M, Tamura A, Suzuki R, Hosokawa Y, Suzuki H, Ota H, Nakamura S, Morishima Y, Taniwaki M, Seto M (November 1999). "A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue". Oncogene 18 (42): 5785–94. doi:10.1038/sj.onc.1203018. PMID 10523859. 
  4. ↑ Ruefli-Brasse AA, French DM, Dixit VM (2003). "Regulation of NF-kappaB-dependent lymphocyte activation and development by paracaspase". Science 302 (5650): 1581–4. doi:10.1126/science.1090769. PMID 14576442. https://semanticscholar.org/paper/74dcf0a2b3df77d05e12ad299887d384b389a179. 
  5. ↑ Ruland J, Duncan GS, Wakeham A, Mak TW (2003). "Differential requirement for Malt1 in T and B cell antigen receptor signaling". Immunity 19 (5): 749–58. doi:10.1016/S1074-7613(03)00293-0. PMID 14614861. 
  6. ↑ McKinnon, Margaret L.; Rozmus, Jacob; Fung, Shan-Yu; Hirschfeld, Aaron F.; Del Bel, Kate L.; Thomas, Leah; Marr, Nico; Martin, Spencer D. et al. (2014-05). "Combined immunodeficiency associated with homozygous MALT1 mutations". Journal of Allergy and Clinical Immunology 133 (5): 1458–1462.e7. doi:10.1016/j.jaci.2013.10.045. https://linkinghub.elsevier.com/retrieve/pii/S0091674913017065. 
  7. ↑ Jabara, Haifa H.; Ohsumi, Toshiro; Chou, Janet; Massaad, Michel J.; Benson, Halli; Megarbane, Andre; Chouery, Eliane; Mikhael, Raymond et al. (2013-07). "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency". Journal of Allergy and Clinical Immunology 132 (1): 151–158. doi:10.1016/j.jaci.2013.04.047. PMID 23727036. PMC PMC3700575. https://linkinghub.elsevier.com/retrieve/pii/S0091674913006945. 
  8. ↑ Punwani, Divya; Wang, Haopeng; Chan, Alice Y.; Cowan, Morton J.; Mallott, Jacob; Sunderam, Uma; Mollenauer, Marianne; Srinivasan, Rajgopal et al. (2015-02). "Combined Immunodeficiency Due to MALT1 Mutations, Treated by Hematopoietic Cell Transplantation". Journal of Clinical Immunology 35 (2): 135–146. doi:10.1007/s10875-014-0125-1. ISSN 0271-9142. PMID 25627829. PMC PMC4352191. http://link.springer.com/10.1007/s10875-014-0125-1. 
  9. ↑ Demeyer, Annelies; Van Nuffel, Elien; Baudelet, Griet; Driege, Yasmine; Kreike, Marja; Muyllaert, David; Staal, Jens; Beyaert, Rudi (2019-10-01). "MALT1-Deficient Mice Develop Atopic-Like Dermatitis Upon Aging". Frontiers in Immunology 10. doi:10.3389/fimmu.2019.02330. ISSN 1664-3224. PMID 31632405. PMC PMC6779721. https://www.frontiersin.org/article/10.3389/fimmu.2019.02330/full. 
  10. ↑ Gilis, Elisabeth; Gaublomme, Djoere; Staal, Jens; Venken, Koen; Dhaenens, Maarten; Lambrecht, Stijn; Coudenys, Julie; Decruy, Tine et al. (2019-12). "Deletion of Mucosa‐Associated Lymphoid Tissue Lymphoma Translocation Protein 1 in Mouse T Cells Protects Against Development of Autoimmune Arthritis but Leads to Spontaneous Osteoporosis". Arthritis & Rheumatology 71 (12): 2005–2015. doi:10.1002/art.41029. ISSN 2326-5191. https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.41029. 
  11. ↑ Wegener E, Krappmann D (2007). "CARD-Bcl10-Malt1 signalosomes: missing link to NF-kappaB". Sci STKE 2007 (384): pe21. doi:10.1126/stke.3842007pe21. PMID 17473310. 
  12. ↑ "Entrez Gene: MALT1 mucosa associated lymphoid tissue lymphoma translocation gene 1".
  13. ↑ 13.0 13.1 Gewies, Andreas; Gorka, Oliver; Bergmann, Hanna; Pechloff, Konstanze; Petermann, Franziska; Jeltsch, Katharina M.; Rudelius, Martina; Kriegsmann, Mark et al. (2014-11). "Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation". Cell Reports 9 (4): 1292–1305. doi:10.1016/j.celrep.2014.10.044. https://linkinghub.elsevier.com/retrieve/pii/S2211124714009139. 
  14. ↑ Yu, Jong W.; Hoffman, Sandy; Beal, Allison M.; Dykon, Angela; Ringenberg, Michael A.; Hughes, Anna C.; Dare, Lauren; Anderson, Amber D. et al. (2015-05-12). Krieg, Andreas. ed. "MALT1 Protease Activity Is Required for Innate and Adaptive Immune Responses". PLOS ONE 10 (5): e0127083. doi:10.1371/journal.pone.0127083. ISSN 1932-6203. PMID 25965667. PMC PMC4428694. https://dx.plos.org/10.1371/journal.pone.0127083. 
  15. ↑ Jaworski, Maike; Marsland, Ben J; Gehrig, Jasmine; Held, Werner; Favre, Stéphanie; Luther, Sanjiv A; Perroud, Mai; Golshayan, Déla et al. (2014-12). "Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity". The EMBO Journal 33 (23): 2765–2781. doi:10.15252/embj.201488987. ISSN 0261-4189. PMID 25319413. PMC PMC4282555. https://www.embopress.org/doi/10.15252/embj.201488987. 
  16. ↑ Demeyer, Annelies; Skordos, Ioannis; Driege, Yasmine; Kreike, Marja; Hochepied, Tino; Baens, Mathijs; Staal, Jens; Beyaert, Rudi (2019-08-14). "MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner". Frontiers in Immunology 10. doi:10.3389/fimmu.2019.01898. ISSN 1664-3224. PMID 31474984. PMC PMC6702287. https://www.frontiersin.org/article/10.3389/fimmu.2019.01898/full. 
  17. ↑ Rosenbaum, Marc; Gewies, Andreas; Pechloff, Konstanze; Heuser, Christoph; Engleitner, Thomas; Gehring, Torben; Hartjes, Lara; Krebs, Sabrina et al. (2019-05-28). "Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells". Nature Communications 10 (1). doi:10.1038/s41467-019-10203-2. ISSN 2041-1723. PMID 31138793. PMC PMC6538646. https://www.nature.com/articles/s41467-019-10203-2. 
  18. ↑ Rosenbaum, Marc; Schnalzger, Theresa; Engleitner, Thomas; Weiß, Christin; Mishra, Ritu; Mibus, Cora; Mitterer, Theresa; Rad, Roland et al. (2022-01). "MALT1 protease function in regulatory T cells induces MYC activity to promote mitochondrial function and cellular expansion". European Journal of Immunology 52 (1): 85–95. doi:10.1002/eji.202149355. ISSN 0014-2980. https://onlinelibrary.wiley.com/doi/10.1002/eji.202149355. 
  19. ↑ Moud, Bahareh Nemati; Ober, Franziska; O’Neill, Thomas J.; Krappmann, Daniel (2024-05-28). "MALT1 substrate cleavage: what is it good for?". Frontiers in Immunology 15. doi:10.3389/fimmu.2024.1412347. ISSN 1664-3224. PMID 38863711. PMC PMC11165066. https://www.frontiersin.org/articles/10.3389/fimmu.2024.1412347/full. 
  20. ↑ Martin, Kea; Junker, Ursula; Tritto, Elaine; Sutter, Esther; Rubic-Schneider, Tina; Morgan, Hannah; Niwa, Satoru; Li, Jianping et al. (2020-04-30). "Pharmacological Inhibition of MALT1 Protease Leads to a Progressive IPEX-Like Pathology". Frontiers in Immunology 11. doi:10.3389/fimmu.2020.00745. ISSN 1664-3224. PMID 32425939. PMC PMC7203682. https://www.frontiersin.org/article/10.3389/fimmu.2020.00745/full. 
  21. ↑ Demeyer, Annelies; Driege, Yasmine; Skordos, Ioannis; Coudenys, Julie; Lemeire, Kelly; Elewaut, Dirk; Staal, Jens; Beyaert, Rudi (2020-10). "Long-Term MALT1 Inhibition in Adult Mice Without Severe Systemic Autoimmunity". iScience 23 (10): 101557. doi:10.1016/j.isci.2020.101557. PMID 33083726. PMC PMC7522757. https://linkinghub.elsevier.com/retrieve/pii/S2589004220307495. 
  22. ↑ Azambuja, Juliana Hofstätter; Yerneni, Saigopalakrishna S.; Maurer, Lisa M.; Crentsil, Hannah E.; Debom, Gabriela N.; Klei, Linda; Smyers, Mei; Sneiderman, Chaim T. et al. (2024-09-27). MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression. bioRxiv. doi:10.1101/2024.09.26.614808. https://www.biorxiv.org/content/10.1101/2024.09.26.614808v1. Retrieved 2024-10-23. 
  23. ↑ Uren AG, O'Rourke K, Aravind LA, Pisabarro MT, Seshagiri S, Koonin EV, Dixit VM (October 2000). "Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma". Mol. Cell 6 (4): 961–7. doi:10.1016/S1097-2765(05)00086-9. PMID 11090634. 
  24. ↑ Hamilton, Kristia S.; Phong, Binh; Corey, Catherine; Cheng, Jing; Gorentla, Balachandra; Zhong, Xiaoping; Shiva, Sruti; Kane, Lawrence P. (2014-06-10). "T Cell Receptor–Dependent Activation of mTOR Signaling in T Cells Is Mediated by Carma1 and MALT1, But Not Bcl10". Science Signaling 7 (329). doi:10.1126/scisignal.2005169. ISSN 1945-0877. PMID 24917592. PMC PMC4405131. https://www.science.org/doi/10.1126/scisignal.2005169. 
  25. ↑ O'Sullivan, Paul A.; Aidarova, Aigerim; Afonina, Inna S.; Manils, Joan; Thurston, Teresa L. M.; Instrell, Rachael; Howell, Michael; Boeing, Stefan et al. (2024-09-18). "CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation". Biochemical Journal 481 (18): 1143–1171. doi:10.1042/BCJ20240058. ISSN 0264-6021. https://portlandpress.com/biochemj/article/481/18/1143/234816/CARD14-signalosome-formation-is-associated-with. 
  26. ↑ Hachmann, Janna; Snipas, Scott J.; van Raam, Bram J.; Cancino, Erik M.; Houlihan, Emily J.; Poreba, Marcin; Kasperkiewicz, Paulina; Drag, Marcin et al. (2012-04-01). "Mechanism and specificity of the human paracaspase MALT1". Biochemical Journal 443 (1): 287–295. doi:10.1042/BJ20120035. ISSN 0264-6021. PMID 22309193. PMC PMC3304489. https://portlandpress.com/biochemj/article/443/1/287/80330/Mechanism-and-specificity-of-the-human-paracaspase. 
  27. ↑ Hulpiau, Paco; Driege, Yasmine; Staal, Jens; Beyaert, Rudi (2016-03). "MALT1 is not alone after all: identification of novel paracaspases". Cellular and Molecular Life Sciences 73 (5): 1103–1116. doi:10.1007/s00018-015-2041-9. ISSN 1420-682X. PMID 26377317. PMC PMC11108557. http://link.springer.com/10.1007/s00018-015-2041-9. 
  28. ↑ Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J, Sun L, Chen ZJ, Marynen P, Beyaert R (2008). "T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20.". Nature Immunology 9 (3): 263–71. doi:10.1038/ni1561. PMID 18223652. 
  29. ↑ 29.0 29.1 Rebeaud F, Hailfinger S, Posevitz-Fejfar A, Tapernoux M, Moser R, Rueda D, Gaide O, Guzzardi M, Iancu EM, Rufer N, Fasel N, Thome M (2008). "The proteolytic activity of the paracaspase MALT1 is key in T cell activation.". Nature Immunology 9 (3): 272–81. doi:10.1038/ni1568. PMID 18264101. 
  30. ↑ Staal J, Driege Y, Bekaert T, Demeyer A, Muyllaert D, Van Damme P, Gevaert K, Beyaert R (2011). "T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1.". EMBO J. 30 (4): 1742–52. doi:10.1038/emboj.2011.85. PMID 21448133. PMC 3101995. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3101995/. 
  31. ↑ Hailfinger S, Nogai H, Pelzer C, Jaworski M, Cabalzar K, Charton JE, Guzzardi M, Décaillet C, Grau M, Dörken B, Lenz P, Lenz G, Thome M (2011). "Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines.". Proc Natl Acad Sci U S A 108 (35): 14596–601. doi:10.1073/pnas.1105020108. PMID 21873235. PMC 3167514. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3167514/. 
  32. ↑ Uehata T, Iwasaki H, Vandenbon A, Matsushita K, Hernandez-Cuellar E, Kuniyoshi K, Satoh T, Mino T, Suzuki Y, Standley DM, Tsujimura T, Rakugi H, Isaka Y, Takeuchi O, Akira S (2013). "Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation.". Cell 153 (5): 1036–49. doi:10.1016/j.cell.2013.04.034. PMID 23706741. 
  33. ↑ 33.0 33.1 Jeltsch KM, Hu D, Brenner S, Zöller J, Heinz GA, Nagel D, Vogel KU, Rehage N, Warth SC, Edelmann SL, Gloury R, Martin N, Lohs C, Lech M, Stehklein JE, Geerlof A, Kremmer E, Weber A, Anders HJ, Schmitz I, Schmidt-Supprian M, Fu M, Holtmann H, Krappmann D, Ruland J, Kallies A, Heikenwalder M, Heissmeyer V (2014). "Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation.". Nat Immunol 15 (11): 1079–89. doi:10.1038/ni.3008. PMID 25282160. 
  34. ↑ Baens M, Bonsignore L, Somers R, Vanderheydt C, Weeks SD, Gunnarsson J, Nilsson E, Roth RG, Thome M, Marynen P (2014). "MALT1 auto-proteolysis is essential for NF-κB-dependent gene transcription in activated lymphocytes.". PLOS ONE 9 (8): e103774. doi:10.1371/journal.pone.0103774. PMID 25105596. PMC 4126661. //www.ncbi.nlm.nih.gov/pmc/articles/PMC4126661/. 
  35. ↑ Ginster S, Bardet M, Unterreiner A, Malinverni C, Renner F, Lam S, Freuler F, Gerrits B, Voshol J, Calzascia T, Régnier CH, Renatus M, Nikolay R, Israël L, Bornancin F (2017). "Two Antagonistic MALT1 Auto-Cleavage Mechanisms Reveal a Role for TRAF6 to Unleash MALT1 Activation". PLOS ONE 12 (1): e0169026. doi:10.1371/journal.pone.0169026. PMID 28052131. PMC 5214165. //www.ncbi.nlm.nih.gov/pmc/articles/PMC5214165/. 
  36. ↑ Klein T, Fung SY, Renner F, Blank MA, Dufour A, Kang S, Bolger-Munro M, Scurll JM, Priatel JJ, Schweigler P, Melkko S, Gold MR, Viner RI, Régnier CH, Turvey SE, Overall CM (2015). "The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling.". Nat. Commun. 6: 8777. doi:10.1038/ncomms9777. PMID 26525107. PMC 4659944. //www.ncbi.nlm.nih.gov/pmc/articles/PMC4659944/. 
  37. ↑ Elton L, Carpentier I, Staal J, Driege Y, Haegman M, Beyaert R (2015). "MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-κB signaling.". FEBS J. 283 (3): 403–12. doi:10.1111/febs.13597. PMID 26573773. 
  38. ↑ Douanne T, Gavard J, Bidère N (May 2016). "The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling". Journal of Cell Science 129 (9): 1775–80. doi:10.1242/jcs.185025. PMID 27006117. http://www.hal.inserm.fr/inserm-01311283/file/ArticleEqu15_2016.pdf. 
  39. ↑ Yamasoba D, Sato K, Ichinose T, Imamura T, Koepke L, Joas S, Reith E, Hotter D, Misawa N, Akaki K, Uehata T, Mino T, Miyamoto S, Noda T, Yamashita A, Standley DM, Kirchhoff F, Sauter D, Koyanagi Y, Takeuchi O (May 2019). "N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation". Nature Microbiology 4 (9): 1532–1544. doi:10.1038/s41564-019-0460-3. PMID 31133753. 
  40. ↑ Israël L, Glück A, Berger M, Coral M, Ceci M, Unterreiner A (2021). "CARD10 cleavage by MALT1 restricts lung carcinoma growth in vivo.". Oncogenesis 10 (4): 32. doi:10.1038/s41389-021-00321-2. PMID 33824280. PMC 8024357. //www.ncbi.nlm.nih.gov/pmc/articles/PMC8024357/. 
  41. ↑ 41.0 41.1 41.2 41.3 41.4 41.5 41.6 Bell, Peter A.; Scheuermann, Sophia; Renner, Florian; Pan, Christina L.; Lu, Henry Y.; Turvey, Stuart E.; Bornancin, Frédéric; Régnier, Catherine H. et al. (2022-08-19). "Integrating knowledge of protein sequence with protein function for the prediction and validation of new MALT1 substrates". Computational and Structural Biotechnology Journal 20: 4717–4732. doi:10.1016/j.csbj.2022.08.021. ISSN 2001-0370. PMID 36147669. PMC 9463181. //www.ncbi.nlm.nih.gov/pmc/articles/PMC9463181/. 
  42. ↑ Rosebeck S, Madden L, Jin X, Gu S, Apel IJ, Appert A, Hamoudi RA, Noels H, Sagaert X, Van Loo P, Baens M, Du MQ, Lucas PC, McAllister-Lucas LM (2011). "Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation.". Science 331 (6016): 468–72. doi:10.1126/science.1198946. PMID 21273489. PMC 3124150. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3124150/. 
  43. ↑ Nie Z, Du MQ, McAllister-Lucas LM, Lucas PC, Bailey NG, Hogaboam CM, Lim MS, Elenitoba-Johnson KS (2015). "Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2-MALT1 in MALT lymphoma.". Nat. Commun. 6 (5908): 5908. doi:10.1038/ncomms6908. PMID 25569716. 
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  45. ↑ Hamp I, O'Neill TJ, Plettenburg O, Krappmann D (2021). "A patent review of MALT1 inhibitors (2013-present).". Expert Opin Ther Pat 31 (12): 1079–1096. doi:10.1080/13543776.2021.1951703. PMID 34214002. https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=34214002. 
  46. ↑ Clinical trial number NCT03900598 for "A Study of JNJ-67856633 in Participants With Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)" at ClinicalTrials.gov
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  48. ↑ Fontan L, Yang C, Kabaleeswaran V, Volpon L, Osborne MJ, Beltran E, Garcia M, Cerchietti L, Shaknovich R, Yang SN, Fang F, Gascoyne RD, Martinez-Climent JA, Glickman JF, Borden K, Wu H, Melnick A (December 2012). "MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo". Cancer Cell 22 (6): 812–24. doi:10.1016/j.ccr.2012.11.003. PMID 23238016. PMC 3984478. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3984478/. 
  49. ↑ Nagel D, Spranger S, Vincendeau M, Grau M, Raffegerst S, Kloo B, Hlahla D, Neuenschwander M, Peter von Kries J, Hadian K, Dörken B, Lenz P, Lenz G, Schendel DJ, Krappmann D (December 2012). "Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL". Cancer Cell 22 (6): 825–37. doi:10.1016/j.ccr.2012.11.002. PMID 23238017. 
  50. ↑ Jacobs KA, André-Grégoire G, Maghe C, Li Y, Thys A, Harford-Wright E, Trillet K, Douanne T, Frénel JS, Bidère N, Gavard J (2019-01-01). "Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival". bioRxiv: 582221. doi:10.1101/582221. 
  51. ↑ Konczalla, Leonie; Perez, Daniel R.; Wenzel, Nadine; Wolters-Eisfeld, Gerrit; Klemp, Clarissa; Lüddeke, Johanna; Wolski, Annika; Landschulze, Dirk et al. (2019-07-10). "Biperiden and Mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer". International Journal of Cancer 146 (6): 1618–1630. doi:10.1002/ijc.32567. ISSN 1097-0215. PMID 31291468. 
  52. ↑ Scott DA, Hatcher JM, Liu H, Fu M, Du G, Fontán L, Us I, Casalena G, Qiao Q, Wu H, Melnick A, Gray NS (May 2019). "Quinoline and thiazolopyridine allosteric inhibitors of MALT1". Bioorganic & Medicinal Chemistry Letters 29 (14): 1694–1698. doi:10.1016/j.bmcl.2019.05.040. PMID 31129051. 
  53. ↑ Bardet M, Unterreiner A, Malinverni C, Lafossas F, Vedrine C, Boesch D, Kolb Y, Kaiser D, Glück A, Schneider MA, Katopodis A, Renatus M, Simic O, Schlapbach A, Quancard J, Régnier CH, Bold G, Pissot-Soldermann C, Carballido JM, Kovarik J, Calzascia T, Bornancin F (January 2018). "The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition". Immunology and Cell Biology 96 (1): 81–99. doi:10.1111/imcb.1018. PMID 29359407. 
  54. ↑ Quancard J, Klein T, Fung SY, Renatus M, Hughes N, Israël L, Priatel JJ, Kang S, Blank MA, Viner RI, Blank J, Schlapbach A, Erbel P, Kizhakkedathu J, Villard F, Hersperger R, Turvey SE, Eder J, Bornancin F, Overall CM (March 2019). "An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient". Nature Chemical Biology 15 (3): 304–313. doi:10.1038/s41589-018-0222-1. PMID 30692685. 
  55. ↑ 55.0 55.1 Cain, Chris (2014-02-06). "Germinating MALT1". SciBX: Science-Business EXchange 7 (5): 133. doi:10.1038/scibx.2014.133. 
  56. ↑ Schiesser S, Hajek P, Pople HE, Käck H, Öster L, Cox RJ (October 2021). "Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors". European Journal of Medicinal Chemistry 227: 113925. doi:10.1016/j.ejmech.2021.113925. PMID 34742013. https://orca.cardiff.ac.uk/id/eprint/146131/1/PP.pdf. 
  57. ↑ "India's first-in-class MALT1 blocker deal". Nature Biotechnology 37 (2): 112. 2019-02-04. doi:10.1038/s41587-019-0026-1. PMID 30718871. 
  58. ↑ Gooyit, M.; Payne, A.; Carvalheda, C.; Evans, D.; Radoux, C.; Richards, S.; Besnard, J.; Varzandeh, S. et al. (2023-10). "832P Characterisation of EXS73565: A potent and selective MALT1 inhibitor with low drug-drug interaction risk and potential in lymphoma". Annals of Oncology 34: S546–S547. doi:10.1016/j.annonc.2023.09.696. https://linkinghub.elsevier.com/retrieve/pii/S0923753423015326. 
  59. ↑ Lim SM, Jeong Y, Lee S, Im H, Tae HS, Kim BG, Park HD, Park J, Hong S (November 2015). "Identification of β-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma". Journal of Medicinal Chemistry 58 (21): 8491–502. doi:10.1021/acs.jmedchem.5b01415. PMID 26496175. 
  60. ↑ Tran TD, Wilson BA, Henrich CJ, Staudt LM, Krumpe LR, Smith EA, King J, Wendt KL, Stchigel AM, Miller AN, Cichewicz RH, O'Keefe BR, Gustafson KR (January 2019). "Secondary Metabolites from the Fungus Dictyosporium sp. and Their MALT1 Inhibitory Activities". Journal of Natural Products 82 (1): 154–162. doi:10.1021/acs.jnatprod.8b00871. PMID 30600998. PMC 7462088. //www.ncbi.nlm.nih.gov/pmc/articles/PMC7462088/. 
  61. ↑ "VIB, CD3 and Galapagos NV enter license deal for the development of MALT1 inhibitors". Science|Business. Retrieved 2019-05-31.
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  63. ↑ Naing, A.; Park, J.C.; Klempner, S.J.; Khan, S.; Pearson, P.; Lufkin, J.; Keller, P.; Youssoufian, H. et al. (2023-10). "1033P First-in-human study of MALT1 inhibitor MPT-0118: Results from monotherapy dose escalation in advanced or metastatic refractory solid tumors". Annals of Oncology 34: S627–S628. doi:10.1016/j.annonc.2023.09.2172. https://linkinghub.elsevier.com/retrieve/pii/S0923753423030090. 
  64. ↑ Yin, Wu; Ye, Min; Marshall, Netonia; Tan, Joanne BL; Paull, Evan; Nie, Zhe; Trzoss, MIchael; Krilov, Goran et al. (2023-11-02). "Sgr-1505 Is a Potent MALT1 Protease Inhibitor with a Potential Best-in-Class Profile". Blood 142 (Supplement 1): 2997–2997. doi:10.1182/blood-2023-190985. ISSN 0006-4971. https://ashpublications.org/blood/article/142/Supplement%201/2997/500137/Sgr-1505-Is-a-Potent-MALT1-Protease-Inhibitor-with. 
  65. ↑ O'Neil, Bert H.; Solis, Willy; Vidal-Cardenas, Sofia; Uttamsingh, Shailaja; Kumar, Abhijeet (2022-11-15). "A First-in-Human Phase 1 Dose Escalation and Expansion Study of the Oral CARD11-BCL10-MALT1 Signaling Pathway Inhibitor XL114 in Patients with Non-Hodgkin's Lymphoma". Blood 140 (Supplement 1): 12055–12056. doi:10.1182/blood-2022-167824. ISSN 0006-4971. https://ashpublications.org/blood/article/140/Supplement%201/12055/489490/A-First-in-Human-Phase-1-Dose-Escalation-and. 
  66. ↑ Biswas, Subhabrata; Chalishazar, Aditi; Helou, Ynes; DiSpirito, Joanna; DeChristopher, Brian; Chatterjee, Devin; Merselis, Leidy; Vincent, Benjamin et al. (2022-05-09). "Pharmacological Inhibition of MALT1 Ameliorates Autoimmune Pathogenesis and Can Be Uncoupled From Effects on Regulatory T-Cells". Frontiers in Immunology 13. doi:10.3389/fimmu.2022.875320. ISSN 1664-3224. PMID 35615349. PMC PMC9125252. https://www.frontiersin.org/articles/10.3389/fimmu.2022.875320/full. 
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