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MALT1 PARACASPASE; MALT1

MALT1 PARACASPASE; MALT1

Alternative titles; symbolsMUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA TRANSLOCATION GENE 1MLTPARACASPASEOther entities represented in this entry:MALT1/API2 FUSIO...

Alternative titles; symbols

  • MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA TRANSLOCATION GENE 1
  • MLT
  • PARACASPASE

Other entities represented in this entry:

  • MALT1/API2 FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: MALT1

Cytogenetic location: 18q21.32 Genomic coordinates (GRCh38): 18:58,671,419-58,754,476 (from NCBI)

▼ Description
The MALT1 gene encodes a caspase-like cysteine protease that is essential for nuclear factor-kappa-B (NFKB; see 164011) activation downstream of cell surface receptors (summary by Jabara et al., 2013).

▼ Cloning and Expression
A t(11;18)(q21;q21) translocation is a characteristic cytogenetic abnormality in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type (Ott et al., 1997). By FISH, Dierlamm et al. (1999) mapped the position of YAC probes on 11q21-q22.31 relative to the breakpoints on chromosome 18. By searching EST databases, they identified a 178-bp fragment that represented an exon of a human gene, which the authors called MLT (MALT lymphoma-associated translocation), that was disrupted by the translocation. The authors stated that a consensus MLT cDNA encodes a 729-amino acid protein, but later revised the number of amino acids to 824 (GenBank AF130356). The 3-prime sequence of MLT encodes 2 putative Ig-like C2-type domains. Sequence analysis of amplified cDNA from a lymphoma patient showed that the 3-prime end of MLT was fused to the 5-prime portion of API2 (601721), an inhibitor of apoptosis located at 11q22. The authors noted that API2 is highly expressed in adult lymphoid tissue.

Using exon amplification and cDNA library screening, Akagi et al. (1999) also identified a cDNA encoding MALT1 at the 18q21 breakpoint region. They found that the cDNA encodes an 813-amino acid protein, apparently a splice variant of the sequence reported by Dierlamm et al. (1999). Northern blot analysis revealed 4.5- and 3.1-kb transcripts that showed highest expression in peripheral blood mononuclear cells, moderate or weak expression in bone marrow, thymus, lymph node, colon, and lung, and no expression in liver. Akagi et al. (1999) also detected expression in hematopoietic cell lines and aberrant expression of transcripts larger than 4.5 kb in 4 of 5 patients with MALT lymphoma; in the other patient, there was only weak expression of normal-sized transcripts.

▼ Mapping
Dierlamm et al. (1999) and Akagi et al. (1999) mapped the MALT1 gene to chromosome 18q21.

▼ Gene Function
Using rodent and human cells, Lucas et al. (2001) found that mouse Bcl10 (603517) activated NF-kappa-B (see 164011) signaling through the IKK complex (see 600664). Bcl10 did not interact directly with the IKK complex, but it instead interacted with the Ig-like domains of MALT1 and promoted MALT1 oligomerization. MALT1 oligomerization activated its C-terminal caspase-like domain, which stimulated the IKK complex and activated downstream NF-kappa-B signaling. The API2/MALT1 fusion protein activated NF-kappa-B signaling through the same downstream signaling factors.

Using mouse models, Ruland et al. (2003) demonstrated that MALT1 is essential for T-cell activation, proliferation, and IL2 (147680) production in response to T-cell receptor ligation and strictly required for signal-specific NFKB activation induced by the T-cell receptor but not TNF-alpha (191160) or IL1 (see 147760) signaling. MALT1 operates downstream of BCL10, controls the catalytic activity of the canonical I-kappa-B kinase complex, and regulates the signaling of JNK (601158) and p38 (600289) MAP kinases. In contrast to BCL10 disruption, however, inactivation of MALT1 has only mild effects on B-cell activation and does not cause defects during neurodevelopment. Thus, Ruland et al. (2003) concluded that MALT1 is an essential regulator of BCL10 signaling that is differentially required depending on cellular context.

Using biochemical and genetic approaches, Wegener et al. (2006) demonstrated that IKKB (IKBKB; 603258) is critical for regulation of the CARMA1 (CARD11; 607210)-BCL10-MALT1 (CBM) complex. They found that IKKB is required not only for initial complex formation, but also for triggering disengagement of BCL10 and MALT1 by phosphorylation of the C terminus of BCL10, thereby negatively influencing T-cell receptor signaling. Wegener et al. (2006) proposed a model in which IKKB is associated with BCL10-MALT1 in resting T cells. Following T-cell activation, protein kinase C-theta (PRKCQ; 600448) phosphorylates CARMA1 and induces association of CARMA1 with BCL10-MALT1. Formation of the BCM complex induces maximal activation of IKK through activation of IKKG (IKBKG; 300248). IKKB phosphorylates BCL10 in its MALT1 interaction domain, causing BCL10 and MALT1 to disassociate, resulting in attenuation of NFKB signaling and cytokine production.

By immunoblot analysis, Coornaert et al. (2008) showed that MALT1 is a functional cysteine protease activated by T-cell receptor stimulation and that it rapidly cleaves A20 (TNFAIP; 191163) after arg439, impairing its NFKB inhibitor function. Coornaert et al. (2008) concluded that A20 is a substrate of MALT1 and that MALT1 proteolytic activity is important in the fine tuning of T cell antigen receptor signaling.

Using immunoprecipitation, immunoblot, and FACS analysis, Ferch et al. (2009) showed that aggressive activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL) cells, but not germinal center B cell-like (GCB) DLBCL, possess constitutively assembled CARD11-BCL10-MALT1 (CBM) complexes that continuously and selectively process A20. Inhibition of MALT1 blocks A20 and BCL10 cleavage, reduces NFKB activity, and decreases the expression of NFKB targets BCLXL (BCL2L1; (600039), IL6 (147620), and IL10 (124092)). Inhibition of MALT1 paracaspase leads to ABC-DLBCL cell death and growth retardation. Ferch et al. (2009) concluded that MALT1 paracaspase activity has a growth-promoting role, specifically in ABC-DLBCL cells, and proposed that MALT1 protease activity is a potential target for pharmacologic treatment of ABC-DLBCL.

Using mouse T cells deficient in the RNase Zc3h12a (610562), Uehata et al. (2013) showed that Zc3h12a was essential for preventing aberrant effector Cd4 (186940)-positive T-cell generation autonomously. Zc3h12a-deficient T cells showed a loss of ability to cleave the 3-prime UTRs of the transcription factor Rel (164910), surface-expressed Ox40 (TNFRSF4; 600315), and the cytokine Il2 (147680). T-cell receptor stimulation of wildtype T cells resulted in cleavage of Zc3h12a at arg111 by Malt1, thus freeing T cells from Zc3h12a-mediated suppression. Malt1 activity was also critical for the stability of Rel, Ox40, and Il2 mRNAs. Uehata et al. (2013) concluded that dynamic control of ZC3H12A activity is critical for controlling T-cell activation.

▼ Cytogenetics
API2/MALT1 Fusion Oncoprotein

To gain insight into the mechanism that generates the t(11;18) translocation in MALT lymphomas, Sato et al. (2001) cloned and sequenced an API2-MALT1 fused transcript as well as genomic DNA of the t(11;18) translocation from a MALT lymphoma. They localized the API2 breakpoint within intron 7. Nucleotide sequence analysis revealed that the genomic breakpoint junction possesses the consensus heptamers of immunoglobulin V(D)J recombination signal sequences, all the matches being completely present on the API2 allele and 5 of 7 matches on the MALT1 allele. These data suggested that the translocation in the MALT lymphoma may have been mediated in part by an aberrant V(D)J recombination event.

In approximately 5 to 10% of gastric MALT lymphomas, evidence of Helicobacter pylori infection is absent. Ye et al. (2003) reviewed the clinical data and histology of 17 such cases and examined them for the t(11;18)(q21;q21) translocation and BCL10 expression pattern. In each case, the absence of H. pylori was confirmed by negative serology and histology/immunohistochemistry. In 5 cases the disease was first treated with antibiotics, and none of them showed any endoscopic or histologic response. Review of the histology failed to identify any apparent difference between gastric MALT lymphomas with or without H. pylori infection. The t(11;18) translocation was identified in 9 (53%) of 17 cases. Two translocation-positive lymphomas were treated by partial gastrectomy and more than 16 years later showed lymphoma relapse in the gastric stump with dissemination to other mucosal sites, poorly responsive to therapy.

Rosebeck et al. (2011) demonstrated that the API2/MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in MALT lymphoma induces proteolytic cleavage of NF-kappa-B-inducing kinase (NIK; 604655) at arginine-325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-kappa-B signaling, enhanced B-cell adhesion, and apoptosis resistance. Rosebeck et al. (2011) concluded that their study revealed the gain-of-function proteolytic activity of a fusion oncoprotein and highlighted the importance of the noncanonical NF-kappa-B pathway in B lymphoproliferative disease.

Translocation t(14;18)(q32;q21)

The MALT1 gene is located approximately 5 Mb centromeric to the BCL2 gene (151430) on 18q21. Sanchez-Izquierdo et al. (2003) reported 2 lymphoma patients, 1 with MALT lymphoma and the other with aggressive marginal zone lymphoma (MZL), with a t(14;18)(q32;q21) translocation cytogenetically identical to the frequent translocation involving BCL2 in B-cell non-Hodgkin lymphoma (see 605027); however, in these 2 cases FISH indicated involvement of the MALT1 gene. There had been other evidence suggesting that genes other than BCL2 in the 18q21 band can account for lymphoma; see, e.g., the follicular-variant-translocation gene (FVT1; 136440).

▼ Molecular Genetics
In 2 sibs, born of consanguineous Lebanese parents, with primary immunodeficiency-12 (IMD12; 615468), Jabara et al. (2013) identified a homozygous mutation in the MALT1 gene (S89I; 604860.0001). The mutation, which was found by homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Patient T cells showed impaired degradation of the NFKB inhibitor I-kappa-B-alpha (NFKB1A; 164008) and decreased IL2 (147680) expression after T-cell activation, and the mutant cDNA failed to rescue defective activation of T cells from Malt1-null mice, consistent with a loss of function. The patients had onset of recurrent bacterial and candidal infections in infancy. The patients died at ages 7 and 13.5 years. Laboratory studies showed normal numbers of lymphocytes, but poor antibody response and decreased T-cell proliferative responses to mitogens. The clinical and laboratory findings were similar to those of patients with IMD11 (615206), which is caused by loss-of-function mutations in the CARD11 gene (607210). The findings showed the importance of MALT1 and the CBM complex for activation of NFKB in proper T-cell function.

In a 15-year-old girl, born of consanguineous Kurdish parents, with IMD12 and recurrent infections since infancy, McKinnon et al. (2014) identified a homozygous missense mutation in the MALT1 gene (W580S; 604860.0002). The mutation was found by whole-exome sequencing and segregated with the disorder. Functional studies showed that the mutant protein had lost both paracaspase and scaffolding activity. Although lymphocyte numbers were normal, there was impaired B-cell differentiation, and CD3+ T cells showed an absence of proliferation and blast formation as well as impaired degradation of NFKB1A and decreased phosphorylation of NFKB3 (164014).

▼ Animal Model
Ruefli-Brasse et al. (2003) generated mice deficient in Malt1 (paracaspase) by targeted disruption and found that primary T- and B-cell lymphocytes from these mice were defective in antigen receptor-induced NF-kappa-B activation, cytokine production, and proliferation. Paracaspase acts downstream of BCL10 to induce NF-kappa-B activation and is required for the normal development of B cells, indicating that paracaspase provides the missing link between BCL10 and activation of the I-kappa-B kinase complex.

Martin et al. (2019) found that Malt1 protease-deficient (Malt1PD) mice had excessive production of IgG1 and IgE at environmental barrier sites, such as mouth, eyes, and intestinal tract, due to excessive B-cell responses. The excessive humoral response to cecal and food-derived antigens in Malt1PD mice was not because deficiency of Malt1 protease in nonhematopoietic cells disrupted intestinal barrier integrity, but because it disrupted intestinal immune homeostasis. Therefore, the lethal inflammatory disease in Malt1PD mice was not due to elevated IgG1 and IgE levels and B-cell responses, but instead was due to T-lymphocytes with contributions from Cd4 and Cd8 T cells. Regulatory T cells (Tregs) in Malt1PD mice were reduced but retained their functional capacity in vitro, but they were not able to prevent expansion of pathogenic T cells in vivo, thereby impairing maintenance of T-cell anergy and leading to lethality.

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 IMMUNODEFICIENCY 12
MALT1, SER89ILE
In 2 sibs, born of consanguineous Lebanese parents, with primary immunodeficiency-12 (IMD12; 615468), Jabara et al. (2013) identified a homozygous c.266G-T transversion in the MALT1 gene, resulting in a ser89-to-ile (S89I) substitution at a highly conserved residue in the CARD domain. The mutation was predicted to disrupt the structure of the domain and render the mutant protein susceptible to degradation. The mutation, which was found by homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The mutation was not present in the dbSNP or 1000 Genomes Project databases, or in 150 ethnically matched controls. Cells from 1 of the patients showed normal amounts of mutant mRNA, but no detectable MALT1 protein. Patient T cells showed decreased expression of IL2 after T-cell activation, and the mutant cDNA failed to rescue defective activation of T cells from Malt1-null mice, consistent with a loss of function. The patients had onset of recurrent bacterial and candidal infections in infancy. The patients died at ages 7 and 13.5 years. Laboratory studies showed normal numbers of lymphocytes, but poor antibody response and decreased T-cell proliferative responses to mitogens.

.0002 IMMUNODEFICIENCY 12
MALT1, TRP580SER
In a 15-year-old girl, born of consanguineous Kurdish parents, with primary immunodeficiency-12 (IMD12; 615468), McKinnon et al. (2014) identified a homozygous c.1739G-C transversion in the MALT1 gene, resulting in a trp580-to-ser (W580S) substitution at a highly conserved residue in the C-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP (build 132), Exome Variant Server, or 1000 Genomes Project databases. The mutant protein was expressed at decreased levels compared to controls, suggesting protein instability. Functional studies showed absence of paracaspase activity as well as an inability of mutant MALT1 to stably bind BCL10 (603517), indicating a lack of scaffold function. Immunophenotyping of patient B cells showed increased numbers of naive B cells, absent marginal zone B cells, and decreased switched memory B cells, consistent with an arrest of B-cell development. However, serum Ig levels were normal except for increased IgE, and the patient was able to mount antibodies against vaccines. CD3+ T cells were increased, with skewing toward the CD4+ T helper subset. Stimulation testing showed an absence of proliferation and blast formation in CD3+ T cells. There was impaired degradation of NFKB1A (164008) and decreased phosphorylation of NFKB3 (164014), which could be rescued by expression of wildtype MALT1.

Tags: 18q21.32