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MALT1 auto-proteolysis is essential for NF-κB-dependent gene transcription in activated lymphocytes.

Baens M, Bonsignore L, Somers R, Vanderheydt C, Weeks SD, Gunnarsson J, Nilsson E, Roth RG, Thome M, Marynen P - PLoS ONE (2014)

Bottom Line: MALT1 cleavage occurred after Arginine 149, between the N-terminal death domain and the first immunoglobulin-like region, and did not affect its proteolytic activity.Jurkat T cells expressing an un-cleavable MALT1-R149A mutant showed unaltered initial IκBα phosphorylation and normal nuclear accumulation of NF-κB subunits.Transcriptome analysis confirmed that MALT1 cleavage after R149 was required to induce NF-κB transcriptional activity in Jurkat T cells.

View Article: PubMed Central - PubMed

Affiliation: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Center for Human Genetics, KU Leuven, Leuven, Belgium.

ABSTRACT
Mucosa-associated lymphoid tissue 1 (MALT1) controls antigen receptor-mediated signalling to nuclear factor κB (NF-κB) through both its adaptor and protease function. Upon antigen stimulation, MALT1 forms a complex with BCL10 and CARMA1, which is essential for initial IκBα phosphorylation and NF-κB nuclear translocation. Parallel induction of MALT1 protease activity serves to inactivate negative regulators of NF-κB signalling, such as A20 and RELB. Here we demonstrate a key role for auto-proteolytic MALT1 cleavage in B- and T-cell receptor signalling. MALT1 cleavage occurred after Arginine 149, between the N-terminal death domain and the first immunoglobulin-like region, and did not affect its proteolytic activity. Jurkat T cells expressing an un-cleavable MALT1-R149A mutant showed unaltered initial IκBα phosphorylation and normal nuclear accumulation of NF-κB subunits. Nevertheless, MALT1 cleavage was required for optimal activation of NF-κB reporter genes and expression of the NF-κB targets IL-2 and CSF2. Transcriptome analysis confirmed that MALT1 cleavage after R149 was required to induce NF-κB transcriptional activity in Jurkat T cells. Collectively, these data demonstrate that auto-proteolytic MALT1 cleavage controls antigen receptor-induced expression of NF-κB target genes downstream of nuclear NF-κB accumulation.

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Model for MALT1 functions in TCR-mediated NF-κB1 activation.A) The adaptor function of MALT1 is required for TCR-mediated activation of the IKK complex. Via formation of the CARMA1/BCL10/MALT1 complex MALT1 controls TRAF6-mediated K63 poly-ubiquitination of the gamma subunit of the IKK complex. Concurrent phosphorylation of IKKβ activates the IKK complex that phosphorylates the NF-κB inhibitor IκB, induces its proteasomal degradation and allows nuclear translocation of NF-κB complexes consisting of p50, p65 and REL. B) Parallel induction of MALT1 protease activity prevents de-ubiquitination of IKKγ and possibly other substrates via A20 cleavage and facilitates DNA binding of p65- or REL-containing NF-κB complexes via RELB cleavage. C) MALT1 auto-proteolysis represents a third level of MALT1 regulation that controls in a TRAF6-dependent and BCL10-independent manner the transcriptional activation of nuclear NF-κB complexes via a yet unknown mechanism.
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pone-0103774-g008: Model for MALT1 functions in TCR-mediated NF-κB1 activation.A) The adaptor function of MALT1 is required for TCR-mediated activation of the IKK complex. Via formation of the CARMA1/BCL10/MALT1 complex MALT1 controls TRAF6-mediated K63 poly-ubiquitination of the gamma subunit of the IKK complex. Concurrent phosphorylation of IKKβ activates the IKK complex that phosphorylates the NF-κB inhibitor IκB, induces its proteasomal degradation and allows nuclear translocation of NF-κB complexes consisting of p50, p65 and REL. B) Parallel induction of MALT1 protease activity prevents de-ubiquitination of IKKγ and possibly other substrates via A20 cleavage and facilitates DNA binding of p65- or REL-containing NF-κB complexes via RELB cleavage. C) MALT1 auto-proteolysis represents a third level of MALT1 regulation that controls in a TRAF6-dependent and BCL10-independent manner the transcriptional activation of nuclear NF-κB complexes via a yet unknown mechanism.

Mentions: MALT1 controls T- and B-cell activation via both its adaptor and protease function. As an adaptor, MALT1 is required for building up the proximal signalling complex that controls the IKK-dependent activation of the canonical NF-κB pathway, as well as the activation of the c-JUN N-terminal kinase (JNK) dependent transcriptional pathway. The protease function of MALT1 apparently serves to promote gene transcription by inactivating negative regulators of NF-κB and JNK signalling, like A20, RELB and CYLD. Moreover, MALT1-dependent cleavage of the RNAse MCPIP1 (also known as Regnase-1) is thought to lead to the stabilization of the resulting transcripts [35]. Auto-processing of MALT1 did not affect these functions, since the processing-deficient R149A mutant showed normal protease activity and an unaltered capacity to promote IKK or JNK activation. The data presented in this study therefore reveal a highly interesting novel aspect of MALT1's function, which is controlled by the auto-proteolytic removal of the N-terminal death domain and the BCL10 binding site. This results in the formation of an active C-terminal p76 fragment of MALT1 that dissociates from BCL10 and oligomerizes to promote NF-κB-dependent transcription in a TRAF6-dependent manner. These findings support a model in which the p76 fragment of MALT1, in combination with TRAF6 and potentially additional components, directly or indirectly affects the transcriptional activity of NF-κB complexes by means that remain to be discovered (Figure 8).


MALT1 auto-proteolysis is essential for NF-κB-dependent gene transcription in activated lymphocytes.

Baens M, Bonsignore L, Somers R, Vanderheydt C, Weeks SD, Gunnarsson J, Nilsson E, Roth RG, Thome M, Marynen P - PLoS ONE (2014)

Model for MALT1 functions in TCR-mediated NF-κB1 activation.A) The adaptor function of MALT1 is required for TCR-mediated activation of the IKK complex. Via formation of the CARMA1/BCL10/MALT1 complex MALT1 controls TRAF6-mediated K63 poly-ubiquitination of the gamma subunit of the IKK complex. Concurrent phosphorylation of IKKβ activates the IKK complex that phosphorylates the NF-κB inhibitor IκB, induces its proteasomal degradation and allows nuclear translocation of NF-κB complexes consisting of p50, p65 and REL. B) Parallel induction of MALT1 protease activity prevents de-ubiquitination of IKKγ and possibly other substrates via A20 cleavage and facilitates DNA binding of p65- or REL-containing NF-κB complexes via RELB cleavage. C) MALT1 auto-proteolysis represents a third level of MALT1 regulation that controls in a TRAF6-dependent and BCL10-independent manner the transcriptional activation of nuclear NF-κB complexes via a yet unknown mechanism.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4126661&req=5

pone-0103774-g008: Model for MALT1 functions in TCR-mediated NF-κB1 activation.A) The adaptor function of MALT1 is required for TCR-mediated activation of the IKK complex. Via formation of the CARMA1/BCL10/MALT1 complex MALT1 controls TRAF6-mediated K63 poly-ubiquitination of the gamma subunit of the IKK complex. Concurrent phosphorylation of IKKβ activates the IKK complex that phosphorylates the NF-κB inhibitor IκB, induces its proteasomal degradation and allows nuclear translocation of NF-κB complexes consisting of p50, p65 and REL. B) Parallel induction of MALT1 protease activity prevents de-ubiquitination of IKKγ and possibly other substrates via A20 cleavage and facilitates DNA binding of p65- or REL-containing NF-κB complexes via RELB cleavage. C) MALT1 auto-proteolysis represents a third level of MALT1 regulation that controls in a TRAF6-dependent and BCL10-independent manner the transcriptional activation of nuclear NF-κB complexes via a yet unknown mechanism.
Mentions: MALT1 controls T- and B-cell activation via both its adaptor and protease function. As an adaptor, MALT1 is required for building up the proximal signalling complex that controls the IKK-dependent activation of the canonical NF-κB pathway, as well as the activation of the c-JUN N-terminal kinase (JNK) dependent transcriptional pathway. The protease function of MALT1 apparently serves to promote gene transcription by inactivating negative regulators of NF-κB and JNK signalling, like A20, RELB and CYLD. Moreover, MALT1-dependent cleavage of the RNAse MCPIP1 (also known as Regnase-1) is thought to lead to the stabilization of the resulting transcripts [35]. Auto-processing of MALT1 did not affect these functions, since the processing-deficient R149A mutant showed normal protease activity and an unaltered capacity to promote IKK or JNK activation. The data presented in this study therefore reveal a highly interesting novel aspect of MALT1's function, which is controlled by the auto-proteolytic removal of the N-terminal death domain and the BCL10 binding site. This results in the formation of an active C-terminal p76 fragment of MALT1 that dissociates from BCL10 and oligomerizes to promote NF-κB-dependent transcription in a TRAF6-dependent manner. These findings support a model in which the p76 fragment of MALT1, in combination with TRAF6 and potentially additional components, directly or indirectly affects the transcriptional activity of NF-κB complexes by means that remain to be discovered (Figure 8).

Bottom Line: MALT1 cleavage occurred after Arginine 149, between the N-terminal death domain and the first immunoglobulin-like region, and did not affect its proteolytic activity.Jurkat T cells expressing an un-cleavable MALT1-R149A mutant showed unaltered initial IκBα phosphorylation and normal nuclear accumulation of NF-κB subunits.Transcriptome analysis confirmed that MALT1 cleavage after R149 was required to induce NF-κB transcriptional activity in Jurkat T cells.

View Article: PubMed Central - PubMed

Affiliation: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Center for Human Genetics, KU Leuven, Leuven, Belgium.

ABSTRACT
Mucosa-associated lymphoid tissue 1 (MALT1) controls antigen receptor-mediated signalling to nuclear factor κB (NF-κB) through both its adaptor and protease function. Upon antigen stimulation, MALT1 forms a complex with BCL10 and CARMA1, which is essential for initial IκBα phosphorylation and NF-κB nuclear translocation. Parallel induction of MALT1 protease activity serves to inactivate negative regulators of NF-κB signalling, such as A20 and RELB. Here we demonstrate a key role for auto-proteolytic MALT1 cleavage in B- and T-cell receptor signalling. MALT1 cleavage occurred after Arginine 149, between the N-terminal death domain and the first immunoglobulin-like region, and did not affect its proteolytic activity. Jurkat T cells expressing an un-cleavable MALT1-R149A mutant showed unaltered initial IκBα phosphorylation and normal nuclear accumulation of NF-κB subunits. Nevertheless, MALT1 cleavage was required for optimal activation of NF-κB reporter genes and expression of the NF-κB targets IL-2 and CSF2. Transcriptome analysis confirmed that MALT1 cleavage after R149 was required to induce NF-κB transcriptional activity in Jurkat T cells. Collectively, these data demonstrate that auto-proteolytic MALT1 cleavage controls antigen receptor-induced expression of NF-κB target genes downstream of nuclear NF-κB accumulation.

Show MeSH
Related in: MedlinePlus