# WikiJournal Preprints/MALT1

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This article is an unpublished pre-print undergoing public peer review organised by the WikiJournal of Science.
First submitted: 6 Feb 2023 Reviewer comments
QID: Q116768205
Suggested (provisional) preprint citation format: Jens Staal. "MALT1". WikiJournal Preprints. Wikidata Q116768205.
License:
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction, provided the original author and source are credited.
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Lara Heller Achim Schlapbach

## Article information

Submitting author: Jens Staal  Additional contributors: Wikipedia community
* ↑ Ghent University
* ↑ jens.staal@irc.vib-ugent.be

## Function

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 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. The osteoporosis and atopic dermatitis phenotypes have also been replicated in Malt1 knock out mice. 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. 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. 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, and conditional mutant mice have shown that this MALT1 protease-dependent immune regulation is taking place in T cells, and especially in regulatory T cells. The lethal autoimmunity is driven by IFNγ-producing T cells. 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. Interestingly, it seems like MALT1 protease inhibition in adult animals leads to a less severe autoimmunity, 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.

## Interactions

MALT1 has been shown to interact with BCL10, 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.

## Protease substrates

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, and for A20 it has been shown that the P5 leucine (LGASR) is required for A20 cleavage. Currently known protease substrates are (in order of reported discovery):
MALT1 protease substrates :
| Substrate | Cleavage sequence |
| A20 (TNFAIP3) | LGASR/G |
| BCL10 | LRSR/T |
| CYLD | FMSR/G |
| RELB | LVSR/G |
| regnase-1/MCPIP1 (ZC3H12A) | LVPR/G |
| Roquin-1(RC3H1) | LIPR/G |
| Roquin-2(RC3H2) | LISR/S |
| MALT1 auto-proteolysis | LCCR/A |
| MALT1 auto-proteolysis | HCSR/T |
| HOIL1 (RBCK1) | LQPR/G |
| N4BP1 | FVSR/G |
| CARD10 | LRCR/G |
| ZC3H12D | LVPR/G |
| ZC3H12B | LVPR/G |
| TAB3 | LQSR/G |
| CASP10 | LVSR/G |
| CILK1 | LISR/S |
| ILDR2 | GASR/G LVSR/T GASR/G |
| TANK | HIPR/V |
Specifically by the oncogenic IAP2-MALT1 fusion:
* NIK
* LIMA1

## Protease inhibitors

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

#### Active site inhibitors

* 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.
* A molecular modeling approach led to the development of the small molecule active site inhibitor MI-2.

#### Allosteric inhibitors

* 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.
* Biperiden, like phenothiazines, act as a MALT1 protease inhibitor and show promising results against pancreatic cancer.
* Quinoline and thiazolopyridine allosteric MALT1 protease inhibitors have been demonstrated to work in mouse disease models.
* Novartis is developing pyrazolopyrimidine derivative MALT1 protease inhibitors.
* AstraZeneca is developing MALT1 protease inhibitors.
* Lupin and AbbVie are developing MALT1 protease inhibitors, in phase 1 clinical trials.
* Excentia has an allosteric inhibitor

#### Natural products

* Analogs of β-Lapachone have been identified as MALT1 protease inhibitors.
* secondary metabolites (oxepinochromenones) from the fungus Dictyosporium show MALT1 protease inhibitory activity.

#### Unknown

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