MALT1#Protease substrates

Genetic ablation of the paracaspase gene in mice and biochemical studies have shown that paracaspase 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{{cite journal | vauthors = Ruefli-Brasse AA, French DM, Dixit VM | title = Regulation of NF-kappaB-dependent lymphocyte activation and development by paracaspase | journal = Science | volume = 302 | issue = 5650 | pages = 1581–1584 | date = November 2003 | pmid = 14576442 | doi = 10.1126/science.1090769 | s2cid = 19381027 | doi-access = free | bibcode = 2003Sci...302.1581R }}{{cite journal | vauthors = Ruland J, Duncan GS, Wakeham A, Mak TW | title = Differential requirement for Malt1 in T and B cell antigen receptor signaling | journal = Immunity | volume = 19 | issue = 5 | pages = 749–758 | date = November 2003 | pmid = 14614861 | doi = 10.1016/S1074-7613(03)00293-0 | doi-access = free }} Two alternatively spliced transcript variants encoding different isoforms have been described for this gene.{{cite web | title = Entrez Gene: MALT1 mucosa associated lymphoid tissue lymphoma translocation gene 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10892}}

In addition, a role for paracaspase 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.{{cite journal | vauthors = Wegener E, Krappmann D | title = CARD-Bcl10-Malt1 signalosomes: missing link to NF-kappaB | journal = Science's STKE | volume = 2007 | issue = 384 | pages = pe21 | date = May 2007 | pmid = 17473310 | doi = 10.1126/stke.3842007pe21 | s2cid = 86150342 }}

Sequence analysis proposes that paracaspase 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 domain. 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.

Paracaspase has been shown to have proteolytic activity through its caspase-like domain in T lymphocytes. Cysteine 464 and histidine 414 are crucial for this activity. Like metacaspases, the paracaspase cleaves substrates after an arginine residue. To date, several paracaspase substrates have been described (see below). Bcl10 is cut after arginine 228. This removes the last five amino acids at the C-terminus and is crucial for T cell adhesion to fibronectin, but not for NF-κB activation and IL-2 production. However, using a peptide-based inhibitor (z-VRPR-fmk) of the paracaspase proteolytic activity, it has been shown that this activity is required for a sustain NF-κB activation and IL-2 production, suggesting that paracaspase may have others substrates involved in T cell-mediated NF-κB activation.{{cite journal | vauthors = 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 | title = The proteolytic activity of the paracaspase MALT1 is key in T cell activation | journal = Nature Immunology | volume = 9 | issue = 3 | pages = 272–281 | date = March 2008 | pmid = 18264101 | doi = 10.1038/ni1568 | s2cid = 205361198 }} A20, a deubiquitinase, has been shown to be cut by paracaspase in Human and in mouse. Cells expressing an uncleavable A20 mutant is however still capable to activate NF-κB, but cells expressing the C-terminal or the N-terminal A20 cleavage products activates more NF-κB than cells expressing wild-type A20, indicating that cleavage of A20 leads to its inactivation. Since A20 has been described has an inhibitor of NF-κB, this suggests that paracaspase-mediated A20 cleavage in T lymphocytes is necessary for a proper NF-κB activation.{{cite journal | vauthors = Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J, Sun L, Chen ZJ, Marynen P, Beyaert R | title = T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20 | journal = Nature Immunology | volume = 9 | issue = 3 | pages = 263–271 | date = March 2008 | pmid = 18223652 | doi = 10.1038/ni1561 | s2cid = 29300246 }}

By targeting paracaspase proteolytic activity, it might be possible to develop new drugs that might be useful for the treatment of certain lymphomas or autoimmune disorders.

MALT1 has been shown to interact with BCL10,{{cite journal | vauthors = Uren AG, O'Rourke K, Aravind LA, Pisabarro MT, Seshagiri S, Koonin EV, Dixit VM | title = Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma | journal = Molecular Cell | volume = 6 | issue = 4 | pages = 961–967 | date = October 2000 | pmid = 11090634 | doi = 10.1016/S1097-2765(05)00086-9 | doi-access = free }} TRAF6 and SQSTM1/p62.

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. Currently known protease substrates are (in order of reported discovery):

Specifically by the oncogenic IAP2-MALT1 fusion:

• NIK{{cite journal | vauthors = 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 | title = Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation | journal = Science | volume = 331 | issue = 6016 | pages = 468–472 | date = January 2011 | pmid = 21273489 | pmc = 3124150 | doi = 10.1126/science.1198946 | bibcode = 2011Sci...331..468R }}
• LIMA1{{cite journal | vauthors = Nie Z, Du MQ, McAllister-Lucas LM, Lucas PC, Bailey NG, Hogaboam CM, Lim MS, Elenitoba-Johnson KS | title = Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2-MALT1 in MALT lymphoma | journal = Nature Communications | volume = 6 | issue = 5908 | pages = 5908 | date = January 2015 | pmid = 25569716 | doi = 10.1038/ncomms6908 | doi-access = free | bibcode = 2015NatCo...6.5908N }}

Since MALT1 protease activity is a promising therapeutic target, several different screenings have been performed which have resulted in different types of protease inhibitors.{{cite journal | vauthors = Demeyer A, Staal J, Beyaert R | title = Targeting MALT1 Proteolytic Activity in Immunity, Inflammation and Disease: Good or Bad? | journal = Trends in Molecular Medicine | volume = 22 | issue = 2 | pages = 135–150 | date = February 2016 | pmid = 26787500 | doi = 10.1016/j.molmed.2015.12.004 }} There is active competition between multiple pharma companies and independent research groups in drug development against the MALT1 protease activity.{{cite journal | vauthors = Hamp I, O'Neill TJ, Plettenburg O, Krappmann D | title = A patent review of MALT1 inhibitors (2013-present) | journal = Expert Opinion on Therapeutic Patents | volume = 31 | issue = 12 | pages = 1079–1096 | date = December 2021 | pmid = 34214002 | pmc = | doi = 10.1080/13543776.2021.1951703 | s2cid = 235723498 }}

• Substrate peptide-based active-site inhibitor: Initially described with the metacaspase inhibitor VRPR-fmk. 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.{{ClinicalTrialsGov|NCT03900598|A Study of JNJ-67856633 in Participants With Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)}}
• Phenothiazine compounds like mepazine and chlorpromazine (which have been used clinically for neurological/psychological conditions) have been found to be allosteric inhibitors of MALT1 protease activity.{{cite journal | vauthors = 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 | title = Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL | journal = Cancer Cell | volume = 22 | issue = 6 | pages = 825–837 | date = December 2012 | pmid = 23238017 | doi = 10.1016/j.ccr.2012.11.002 | doi-access = free }}{{Cite journal| doi = 10.1101/582221| pages = 582221| vauthors = Jacobs KA, André-Grégoire G, Maghe C, Li Y, Thys A, Harford-Wright E, Trillet K, Douanne T, Frénel JS, Bidère N, Gavard J | title = Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival| journal = bioRxiv| date = 2019-01-01| doi-access = free}}
• Biperiden, like phenothiazines, act as a MALT1 protease inhibitor and show promising results against pancreatic cancer.{{cite journal | vauthors = Konczalla L, Perez DR, Wenzel N, Wolters-Eisfeld G, Klemp C, Lüddeke J, Wolski A, Landschulze D, Meier C, Buchholz A, Yao D, Hofmann BT, Graß JK, Spriestersbach SL, Grupp K, Schumacher U, Betzel C, Kapis S, Nuguid T, Steinberg P, Püschel K, Sauter G, Bockhorn M, Uzunoglu FG, Izbicki JR, Güngör C, El Gammal AT | title = Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer | journal = International Journal of Cancer | volume = 146 | issue = 6 | pages = 1618–1630 | date = March 2020 | pmid = 31291468 | doi = 10.1002/ijc.32567 | doi-access = free }}
• A molecular modeling approach led to the development of the small molecule active site inhibitor MI-2.{{cite journal | vauthors = 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 | title = MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo | journal = Cancer Cell | volume = 22 | issue = 6 | pages = 812–824 | date = December 2012 | pmid = 23238016 | pmc = 3984478 | doi = 10.1016/j.ccr.2012.11.003 }}
• Analogs of β-Lapachone have been identified as MALT1 protease inhibitors.{{cite journal | vauthors = Lim SM, Jeong Y, Lee S, Im H, Tae HS, Kim BG, Park HD, Park J, Hong S | title = Identification of β-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma | journal = Journal of Medicinal Chemistry | volume = 58 | issue = 21 | pages = 8491–8502 | date = November 2015 | pmid = 26496175 | doi = 10.1021/acs.jmedchem.5b01415 }}
• Quinoline and thiazolopyridine allosteric MALT1 protease inhibitors have been demonstrated to work in mouse disease models.{{cite journal | vauthors = Scott DA, Hatcher JM, Liu H, Fu M, Du G, Fontán L, Us I, Casalena G, Qiao Q, Wu H, Melnick A, Gray NS | title = Quinoline and thiazolopyridine allosteric inhibitors of MALT1 | journal = Bioorganic & Medicinal Chemistry Letters | volume = 29 | issue = 14 | pages = 1694–1698 | date = July 2019 | pmid = 31129051 | doi = 10.1016/j.bmcl.2019.05.040 | s2cid = 167206456 }}
• secondary metabolites (oxepinochromenones) from the fungus Dictyosporium show MALT1 protease inhibitory activity.{{cite journal | vauthors = 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 | title = Secondary Metabolites from the Fungus Dictyosporium sp. and Their MALT1 Inhibitory Activities | journal = Journal of Natural Products | volume = 82 | issue = 1 | pages = 154–162 | date = January 2019 | pmid = 30600998 | pmc = 7462088 | doi = 10.1021/acs.jnatprod.8b00871 | s2cid = 58540523 }}
• Novartis is developing pyrazolopyrimidine derivative MALT1 protease inhibitors.{{cite journal | vauthors = 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 | title = The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition | journal = Immunology and Cell Biology | volume = 96 | issue = 1 | pages = 81–99 | date = January 2018 | pmid = 29359407 | doi = 10.1111/imcb.1018 | s2cid = 36376441 | doi-access = free }}{{cite journal | vauthors = 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 | title = An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient | journal = Nature Chemical Biology | volume = 15 | issue = 3 | pages = 304–313 | date = March 2019 | pmid = 30692685 | doi = 10.1038/s41589-018-0222-1 | s2cid = 59340695 }}
• VIB is developing MALT1 protease inhibitors in collaboration with the Leuven-based spin-off Centre for Drug Design and Discovery (CD3) {{Cite journal| doi = 10.1038/scibx.2014.133| volume = 7| issue = 5| pages = 133| vauthors = Cain C | title = Germinating MALT1| journal = SciBX: Science-Business EXchange| date = 2014-02-06| doi-access = free}}{{Cite web| title = VIB, CD3 and Galapagos NV enter license deal for the development of MALT1 inhibitors| work = Science{{!}}Business| access-date = 2019-05-31| url = https://sciencebusiness.net/network-news/vib-cd3-and-galapagos-nv-enter-license-deal-development-malt1-inhibitors}}
• AstraZeneca is developing MALT1 protease inhibitors.{{cite journal | vauthors = Schiesser S, Hajek P, Pople HE, Käck H, Öster L, Cox RJ | title = Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors | journal = European Journal of Medicinal Chemistry | volume = 227 | issue = | pages = 113925 | date = January 2022 | pmid = 34742013 | pmc = | doi = 10.1016/j.ejmech.2021.113925 | s2cid = 239486242 | url = https://orca.cardiff.ac.uk/id/eprint/146131/ }}
• Lupin and AbbVie are developing MALT1 protease inhibitors.{{cite journal | vauthors = | title = India's first-in-class MALT1 blocker deal | journal = Nature Biotechnology | volume = 37 | issue = 2 | pages = 112 | date = February 2019 | pmid = 30718871 | doi = 10.1038/s41587-019-0026-1 | s2cid = 59603303 | doi-access = free }}
• Chordia therapeutics is entering a clinical trial with a MALT1 protease inhibitor in 2020 {{Cite web| title = Chordia Therapeutics Raises Approximately 27 million USD in Series B Financing| access-date = 2019-05-31| date = 2019-03-29| url = http://www.chordiatherapeutics.com/eng/update/pdf/20190329_EN.pdf}}
• In the "First Time Disclosure Session" at 2024 ACS conference. Schrödinger announced the discovery of their SGR-1505 innhibitor.{{Cite web| title = Hit to development candidate in 10 months: Rapid discovery of a novel, potent MALT1 inhibitor| access-date = 2024-03-20| date = 2024-03-20| url = https://newsite.schrodinger.com/life-science/learn/case-studies/hit-development-candidate-10-months-rapid-discovery-novel-potent-malt1-inhibitor/}}{{Cite press release| title = Schrödinger Highlights Discovery of SGR-1505, Clinical-Stage MALT1 Inhibitor, at American Chemical Society National Meeting| access-date = 2024-03-20| date = 2024-03-20| url = https://www.businesswire.com/news/home/20240320912754/en/Schr%C3%B6dinger-Highlights-Discovery-of-SGR-1505-Clinical-Stage-MALT1-Inhibitor-at-American-Chemical-Society-National-Meeting}}

• Paracaspase

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• {{cite journal | vauthors = Bertoni F, Cavalli F, Cotter FE, Zucca E | title = Genetic alterations underlying the pathogenesis of MALT lymphoma | journal = The Hematology Journal | volume = 3 | issue = 1 | pages = 10–13 | year = 2003 | pmid = 11960389 | doi = 10.1038/sj.thj.6200146 }}

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• {{PDBe-KB2|Q9UDY8|Mucosa-associated lymphoid tissue lymphoma translocation protein 1}}

{{PDB Gallery|geneid=10892}}