USP2a positively regulates TCR-induced NF-κB activation by bridging MALT1-TRAF6

Li, Yang; He, Xiao; Wang, Shuai; Shu, Hong; Liu, Yu

doi:10.1007/s13238-012-2120-8

Cited by 22 publications

(19 citation statements)

References 27 publications

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“…Clearly, the sequence of events that shape the function of MALT1 will need to be further addressed. In particular, ubiquitination/deubiquitination of MALT1 and more generally of the CBMT complex is still incompletely understood despite some recent advances [52, 53]. Based on our data with the MALT1- 4E/A mutant protein (Fig 5C) and the dominant negative TRAF6 522–689 protein (Fig 6B), it is unlikely that TRAF6 is responsible for mono-ubiquitination of MALT1.…”

Section: Discussionmentioning

confidence: 76%

Two Antagonistic MALT1 Auto-Cleavage Mechanisms Reveal a Role for TRAF6 to Unleash MALT1 Activation

et al. 2017

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The paracaspase MALT1 has arginine-directed proteolytic activity triggered by engagement of immune receptors. Recruitment of MALT1 into activation complexes is required for MALT1 proteolytic function. Here, co-expression of MALT1 in HEK293 cells, either with activated CARD11 and BCL10 or with TRAF6, was used to explore the mechanism of MALT1 activation at the molecular level. This work identified a prominent self-cleavage site of MALT1 isoform A (MALT1A) at R781 (R770 in MALT1B) and revealed that TRAF6 can activate MALT1 independently of the CBM. Intramolecular cleavage at R781/R770 removes a C-terminal TRAF6-binding site in both MALT1 isoforms, leaving MALT1B devoid of the two key interaction sites with TRAF6. A previously identified auto-proteolysis site of MALT1 at R149 leads to deletion of the death-domain, thereby abolishing interaction with BCL10. By using MALT1 isoforms and cleaved fragments thereof, as well as TRAF6 WT and mutant forms, this work shows that TRAF6 induces N-terminal auto-proteolytic cleavage of MALT1 at R149 and accelerates MALT1 protein turnover. The MALT1 fragment generated by N-terminal self-cleavage at R149 was labile and displayed enhanced signaling properties that required an intact K644 residue, previously shown to be a site for mono-ubiquitination of MALT1. Conversely, C-terminal self-cleavage at R781/R770 hampered the ability for self-cleavage at R149 and stabilized MALT1 by hindering interaction with TRAF6. C-terminal self-cleavage had limited impact on MALT1A but severely reduced MALT1B proteolytic and signaling functions. It also abrogated NF-κB activation by N-terminally cleaved MALT1A. Altogether, this study provides further insights into mechanisms that regulate the scaffolding and activation cycle of MALT1. It also emphasizes the reduced functional capacity of MALT1B as compared to MALT1A.

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Section: Discussionmentioning

confidence: 76%

Two Antagonistic MALT1 Auto-Cleavage Mechanisms Reveal a Role for TRAF6 to Unleash MALT1 Activation

et al. 2017

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“…To date, several studies have demonstrated that USP2 modulates the NF- κ B signaling pathway [ 30 , 37 , 38 ]. TRAF6, a signal transducer molecule associated with the TLRs and IL-1 receptor, is a potent target of USP2 [ 30 , 39 ]. Therefore, we monitored TRAF6 protein levels after LPS stimulation.…”

Section: Resultsmentioning

confidence: 99%

Ubiquitin-Specific Protease 2 Modulates the Lipopolysaccharide-Elicited Expression of Proinflammatory Cytokines in Macrophage-like HL-60 Cells

Kitamura

Ishino

Shimamoto

et al. 2017

Mediators of Inflammation

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We investigated the regulatory roles of USP2 in mRNA accumulation of proinflammatory cytokines in macrophage-like cells after stimulation with a toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). Human macrophage-like HL-60 cells, mouse macrophage-like J774.1 cells, and mouse peritoneal macrophages demonstrated negative feedback to USP2 mRNA levels after LPS stimulation, suggesting that USP2 plays a significant role in LPS-stimulated macrophages. USP2 knockdown (KD) by short hairpin RNA in HL-60 cells promoted the accumulation of transcripts for 25 of 104 cytokines after LPS stimulation. In contrast, limited induction of cytokines was observed in cells forcibly expressing the longer splice variant of USP2 (USP2A), or in peritoneal macrophages isolated from Usp2a transgenic mice. An ubiquitin isopeptidase-deficient USP2A mutant failed to suppress LPS-induced cytokine expression, suggesting that protein ubiquitination contributes to USP2-mediated cytokine repression. Although USP2 deficiency did not accelerate TNF receptor-associated factor (TRAF) 6-nuclear factor-κB (NF-κB) signaling, it increased the DNA binding ratio of the octamer binding transcription factor (Oct)-1 to Oct-2 in TNF, CXCL8, CCL4, and IL6 promoters. USP2 decreased nuclear Oct-2 protein levels in addition to decreasing the polyubiquitination of Oct-1. In summary, USP2 modulates proinflammatory cytokine induction, possibly through modification of Oct proteins, in macrophages following TLR4 activation.

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“…Second, USP2a hydrolyses Ub K63 from RIP1 thus preventing NF-κB activation while promoting caspasemediated cell death in response to TNFα stimulation in human cells [38]. Two other studies, by contrast, provide controversial results by describing a positive role for USP2a in TNF-R1 dependent NF-κB signalling [39] or in the regulation of TCR-induced NF-κB activation [40]. These discrepancies may be due to dose-dependent effects of USP2 on multiple targets.…”

Section: Discussionmentioning

confidence: 99%

Identifying USPs regulating immune signals in

Engel

Viargues

Mortier

et al. 2014

Cell Communication and Signaling

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Background: Rapid activation of innate immune defences upon microbial infection depends on the evolutionary conserved NF-κB dependent signals which deregulation is frequently associated with chronic inflammation and oncogenesis. These signals are tightly regulated by the linkage of different kinds of ubiquitin moieties on proteins that modify either their activity or their stability. To investigate how ubiquitin specific proteases (USPs) orchestrate immune signal regulation, we created and screened a focused RNA interference library on Drosophila NF-κB-like pathways Toll and Imd in cultured S2 cells, and further analysed the function of selected genes in vivo.

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USP2a positively regulates TCR-induced NF-κB activation by bridging MALT1-TRAF6

Cited by 22 publications

References 27 publications

Two Antagonistic MALT1 Auto-Cleavage Mechanisms Reveal a Role for TRAF6 to Unleash MALT1 Activation

Two Antagonistic MALT1 Auto-Cleavage Mechanisms Reveal a Role for TRAF6 to Unleash MALT1 Activation

Ubiquitin-Specific Protease 2 Modulates the Lipopolysaccharide-Elicited Expression of Proinflammatory Cytokines in Macrophage-like HL-60 Cells

Identifying USPs regulating immune signals in

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