Cleavage by MALT1 induces cytosolic release of A20

Malinverni, Claire; Unterreiner, Adeline; Staal, Jens; Demeyer, Annelies; Galaup, Marion; Luyten, Marcel; Beyaert, Rudi; Bornancin, Frédéric

doi:10.1016/j.bbrc.2010.08.091

Cited by 26 publications

(23 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A20 is generally cleaved by MALT1; thus, the expression level of MALT1 should be negatively correlated with the A20 and MALT1 expression pattern [41]. We found a negative correlation between the MALT1 and A20 expression levels (rs = –0.806, P = <0.0001) in the healthy individual (Figure 2A) and T-ALL patient groups (rs = –0.450, P = 0.041; Figure 2B) as expected.…”

Section: Resultssupporting

confidence: 78%

Characteristics of CARMA1-BCL10-MALT1-A20-NF-κB expression in T cell-acute lymphocytic leukemia

Liao

et al. 2014

Eur J Med Res

View full text Add to dashboard Cite

BackgroundKnowledge of the oncogenic signaling pathways of T-cell acute lymphoblastic leukemia (T-ALL) remains limited. Constitutive aberrant activation of the nuclear factor kappa B (NF-κB) signaling pathway has been detected in various lymphoid malignancies and plays a key role in the development of these carcinomas. The zinc finger-containing protein, A20, is a central regulator of multiple NF-κB-activating signaling cascades. A20 is frequently inactivated by deletions and/or mutations in several B-and T-cell lymphoma subtypes. However, few A20 mutations and polymorphisms have been reported in T-ALL. Thus, it is of interest to analyze the expression characteristics of A20 and its regulating factors, including upstream regulators and the CBM complex, which includes CARMA1, BCL10, and MALT1.MethodsThe expression levels of CARMA1, BCL10, MALT1, A20, and NF-κB were detected in peripheral blood mononuclear cells (PBMCs) from 21 patients with newly diagnosed T-ALL using real-time PCR, and correlations between the aberrant expression of these genes in T-ALL was analyzed. Sixteen healthy individuals, including 10 males and 6 females, served as controls.ResultsSignificantly lower A20 expression was found in T-ALL patients (median: 4.853) compared with healthy individuals (median: 8.748; P = 0.017), and significantly increased expression levels of CARMA1 (median: 2.916; P = 0.034), BCL10 (median: 0.285; P = 0.033), and MALT1 (median: 1.201; P = 0.010) were found in T-ALL compared with the healthy individuals (median: 1.379, 0.169, and 0.677, respectively). In contrast, overexpression of NF-κB (median: 0.714) was found in T-ALL compared with healthy individuals (median: 0.335; P = 0.001). A negative correlation between the MALT1 and A20 expression levels and a positive correlation between CARMA1 and BCL10 were found in T-ALL and healthy individuals. However, no negative correlation was found between A20 and NF-κB and the MALT1 and NF-κB expression level in the T-ALL group.ConclusionsWe characterized the expression of the CARMA-BCL10-MALT1-A20-NF-κB pathway genes in T-ALL. Overexpression of CARMA-BCL10-MALT in T-ALL may contribute to the constitutive cleavage and inactivation of A20, which enhances NF-κB signaling and may be related to T-ALL pathogenesis.

show abstract

Section: Resultssupporting

confidence: 78%

Characteristics of CARMA1-BCL10-MALT1-A20-NF-κB expression in T cell-acute lymphocytic leukemia

Liao

et al. 2014

Eur J Med Res

View full text Add to dashboard Cite

show abstract

“…MALT1-mediated cleavage of A20 separates its N-terminal de-ubiquitinating domain from the C-terminal substrate-binding domain, which led to the suggestion that A20 cleavage might serve to remove the de-ubiquitinating domain from A20 molecules associated with specific NF-κB signaling molecules, thereby preserving activating ubiquitination events. Recently, A20 cleavage by MALT1 was found to induce the cytosolic release of the N-terminal fragment of A20 from a particulate and insoluble cell fraction, suggesting that loss of compartmentalization might also contribute to MALT1-mediated dampening of A20 function [123]. Bcl10 cleavage could not be linked with altered NF-κB signaling, but is required for TCR-induced cell adhesion to fibronectin [119].…”

Section: The Paracaspase Malt1: Working Double Shifts As a Scaffold Amentioning

confidence: 98%

Regulation of NF-κB signaling by caspases and MALT1 paracaspase

2010

Self Cite

View full text Add to dashboard Cite

Caspases are intracellular proteases that are best known for their function in apoptosis signaling. It has become evident that many caspases also function in other signaling pathways that propagate cell proliferation and inflammation, but studies on the inflammatory function of caspases have mainly been limited to caspase-1-mediated cytokine processing. Emerging evidence, however, indicates an important contribution of caspases as mediators or regulators of nuclear factor-κB (NF-κB) signaling, which plays a key role in inflammation and immunity. Much still needs to be learned about the mechanisms that govern the activation and regulation of NF-κB by caspases, and this review provides an update of this area. Whereas apoptosis signaling is dependent on the catalytic activity of caspases, they mainly act as scaffolding platforms for other signaling proteins in the case of NF-κB signaling. Caspase proteolytic activity, however, counteracts the pro-survival function of NF-κB by cleaving specific signaling molecules. A striking exception is the paracaspase mucosa-associated lymphoid tissue 1 (MALT1), whose adaptor and proteolytic activity are both needed to initiate a full blown NF-κB response in antigen-stimulated lymphocytes. Understanding the role of caspases and MALT1 in the regulation of NF-κB signaling is of high interest for therapeutic immunomodulation.

show abstract

“…* and ** refer to A20 fragments resulting from cleavage at secondary, uncharacterized sites. 39 Cleavage at these sites is enhanced when the major cleavage site (R439) is compromised. stringent.…”

Section: The Ligand Binds In An Extended Conformationmentioning

confidence: 99%

Structural Determinants of MALT1 Protease Activity

Wiesmann

Leder

Blank

et al. 2012

Journal of Molecular Biology

143

View full text Add to dashboard Cite

The formation of the CBM (CARD11-BCL10-MALT1) complex is pivotal for antigen-receptor-mediated activation of the transcription factor NF-κB. Signaling is dependent on MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), which not only acts as a scaffolding protein but also possesses proteolytic activity mediated by its caspase-like domain. It remained unclear how the CBM activates MALT1. Here, we provide biochemical and structural evidence that MALT1 activation is dependent on its dimerization and show that mutations at the dimer interface abrogate activity in cells. The unliganded protease presents itself in a dimeric yet inactive state and undergoes substantial conformational changes upon substrate binding. These structural changes also affect the conformation of the C-terminal Ig-like domain, a domain that is required for MALT1 activity. Binding to the active site is coupled to a relative movement of caspase and Ig-like domains. MALT1 binding partners thus may have the potential of tuning MALT1 protease activity without binding directly to the caspase domain.

show abstract

Cleavage by MALT1 induces cytosolic release of A20

Cited by 26 publications

References 14 publications

Characteristics of CARMA1-BCL10-MALT1-A20-NF-κB expression in T cell-acute lymphocytic leukemia

Characteristics of CARMA1-BCL10-MALT1-A20-NF-κB expression in T cell-acute lymphocytic leukemia

Regulation of NF-κB signaling by caspases and MALT1 paracaspase

Structural Determinants of MALT1 Protease Activity

Contact Info

Product

Resources

About