scholarly journals Sequential ubiquitination of NLRP3 by RNF125 and Cbl-b limits inflammasome activation and endotoxemia

2020 ◽  
Vol 217 (4) ◽  
Author(s):  
Juan Tang ◽  
Sha Tu ◽  
Guoxin Lin ◽  
Hui Guo ◽  
Chengkai Yan ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Lethal Dose ◽  
E3 Ubiquitin Ligase ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Leucine Rich Repeat ◽  
Nlrp3 Inflammasome Activation ◽  
Repeat Domain ◽  
Nlrp3 Inflammasomes ◽  
Lrr Domain

Aberrant NLRP3 inflammasome activation contributes to the development of endotoxemia. The importance of negative regulation of NLRP3 inflammasomes remains poorly understood. Here, we show that the E3 ubiquitin ligase Cbl-b is essential for preventing endotoxemia induced by a sub-lethal dose of LPS via a caspase-11/NLRP3–dependent manner. Further studies show that NLRP3 undergoes both K63- and K48-linked polyubiquitination. Cbl-b binds to the K63-ubiquitin chains attached to the NLRP3 leucine-rich repeat domain (LRR) via its ubiquitin-associated region (UBA) and then targets NLRP3 at K496 for K48-linked ubiquitination and proteasome-mediated degradation. We also identify RNF125 as an additional E3 ubiquitin ligase that initiates K63-linked ubiquitination of the NLRP3 LRR domain. Therefore, NLRP3 is sequentially ubiquitinated by K63- and K48-linked ubiquitination, thus keeping the NLRP3 inflammasomes in check and restraining endotoxemia.

scholarly journals DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Ioannis Kienes ◽  
Sarah Bauer ◽  
Clarissa Gottschild ◽  
Nora Mirza ◽  
Jens Pfannstiel ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Cytokine ◽  
Inflammasome Activation ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Central Target ◽  
Nlrp3 Inflammasome Activation ◽  
Lrr Domain

Tight regulation of inflammatory cytokine and interferon (IFN) production in innate immunity is pivotal for optimal control of pathogens and avoidance of immunopathology. The human Nod-like receptor (NLR) NLRP11 has been shown to regulate type I IFN and pro-inflammatory cytokine responses. Here, we identified the ATP-dependent RNA helicase DDX3X as a novel binding partner of NLRP11, using co-immunoprecipitation and LC-MS/MS. DDX3X is known to enhance type I IFN responses and NLRP3 inflammasome activation. We demonstrate that NLRP11 can abolish IKKϵ-mediated phosphorylation of DDX3X, resulting in lower type I IFN induction upon viral infection. These effects were dependent on the LRR domain of NLRP11 that we mapped as the interaction domain for DDX3X. In addition, NLRP11 also suppressed NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting that NLRP11 might sequester DDX3X and prevent it from promoting NLRP3-induced inflammasome activation. Taken together, our data revealed DDX3X as a central target of NLRP11, which can mediate the effects of NLRP11 on type I IFN induction as well as NLRP3 inflammasome activation. This expands our knowledge of the molecular mechanisms underlying NLRP11 function in innate immunity and suggests that both NLRP11 and DDX3X might be promising targets for modulation of innate immune responses.

scholarly journals A Novel Degron-mediated Degradation of the RTG Pathway Regulator, Mks1p, by SCFGrr1

2005 ◽  
Vol 16 (10) ◽  
pp. 4893-4904 ◽  
Author(s):  
Zhengchang Liu ◽  
Mário Spírek ◽  
Janet Thornton ◽  
Ronald A. Butow
Keyword(s):  
Transcription Factors ◽  
Ubiquitin Ligase ◽  
Positive Charge ◽  
E3 Ubiquitin Ligase ◽  
Retrograde Signaling ◽  
Yeast Cells ◽  
Leucine Rich Repeat ◽  
Negative Regulators ◽  
Acidic Domain ◽  
Lrr Domain

Yeast cells respond to mitochondrial dysfunction by altering the expression of a subset of nuclear genes, a process known as retrograde signaling (RS). RS terminates with two transcription factors, Rtg1p and Rtg3p. One positive regulator, Rtg2p, and four negative regulators, Lst8p, Mks1p, and the redundant 14-3-3 proteins, Bmh1p and Bmh2p, control RS upstream of Rtg1/3p. Mks1p is negatively regulated by binding to Rtg2p and positively regulated when bound to Bmh1/2p. Here we report that Grr1p, a component of the SCFGrr1 E3 ubiquitin ligase, modulates RS by affecting Mks1p levels. Grr1p polyubiquitinates Mks1p not bound to either Rtg2p or to Bmh1/2p, targeting it for degradation. An acidic domain region of Mks1p constitutes the portable Mks1p degron sequence. We have isolated dominant mutations in Grr1p leading to increased Mks1p degradation. These mutations result in a gain of positive charge on the concave surface of the leucine rich repeat (LRR) domain of Grr1p, the proposed substrate binding site. We propose that Mks1p is a central player of RS and is acted upon by multiple regulators of the pathway.

scholarly journals The E3 Ubiquitin Ligase Tripartite Motif 33 Is Essential for Cytosolic RNA–Induced NLRP3 Inflammasome Activation

2014 ◽  
Vol 193 (7) ◽  
pp. 3676-3682 ◽  
Author(s):  
Leiyun Weng ◽  
Hiroki Mitoma ◽  
Coline Tricot ◽  
Musheng Bao ◽  
Ying Liu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Nlrp3 Inflammasome ◽  
E3 Ubiquitin Ligase ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Tripartite Motif

scholarly journals Hect E3 ubiquitin ligase Tom1 controls Dia2 degradation during the cell cycle

2012 ◽  
Vol 23 (21) ◽  
pp. 4203-4211 ◽  
Author(s):  
Dong-Hwan Kim ◽  
Deanna M. Koepp
Keyword(s):  
Cell Cycle ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
S Phase ◽  
Temperature Sensitive ◽  
Dependent Manner ◽  
Charged Residues ◽  
Phase Progression ◽  
Positively Charged

The ubiquitin proteasome system plays a pivotal role in controlling the cell cycle. The budding yeast F-box protein Dia2 is required for genomic stability and is targeted for ubiquitin-dependent degradation in a cell cycle–dependent manner, but the identity of the ubiquitination pathway is unknown. We demonstrate that the Hect domain E3 ubiquitin ligase Tom1 is required for Dia2 protein degradation. Deletion of DIA2 partially suppresses the temperature-sensitive phenotype of tom1 mutants. Tom1 is required for Dia2 ubiquitination and degradation during G1 and G2/M phases of the cell cycle, whereas the Dia2 protein is stabilized during S phase. We find that Tom1 binding to Dia2 is enhanced in G1 and reduced in S phase, suggesting a mechanism for this proteolytic switch. Tom1 recognizes specific, positively charged residues in a Dia2 degradation/NLS domain. Loss of these residues blocks Tom1-mediated turnover of Dia2 and causes a delay in G1–to–S phase progression. Deletion of DIA2 rescues a delay in the G1–to–S phase transition in the tom1Δ mutant. Together our results suggest that Tom1 targets Dia2 for degradation during the cell cycle by recognizing positively charged residues in the Dia2 degradation/NLS domain and that Dia2 protein degradation contributes to G1–to–S phase progression.

scholarly journals Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling

2021 ◽  
Vol 118 (25) ◽  
pp. e2104944118
Author(s):  
Sara E. Konopelski Snavely ◽  
Michael W. Susman ◽  
Ryan C. Kunz ◽  
Jia Tan ◽  
Srisathya Srinivasan ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Large Scale ◽  
Glycogen Synthase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Dependent Manner ◽  
Casein Kinase 1 ◽  
Downstream Signaling ◽  
Proteomic Screen ◽  
Responsive Element

Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate development [R. T. Moon et al., Development 119, 97–111 (1993); I. Oishi et al., Genes Cells 8, 645–654 (2003)], but its downstream signaling events remain poorly understood. Through a large-scale proteomic screen in mouse embryonic fibroblasts, we identified the E3 ubiquitin ligase Pdzrn3 as a regulatory target of the Wnt5a-Ror pathway. Upon pathway activation, Pdzrn3 is degraded in a β-catenin–independent, ubiquitin-proteasome system–dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, Casein kinase 1, and Glycogen synthase kinase 3 that regulates Pdzrn3 stability. Epistatically, Pdzrn3 is regulated independently of Kif26b, another Wnt5a-Ror effector. Wnt5a-dependent degradation of Pdzrn3 requires phosphorylation of three conserved amino acids within its C-terminal LNX3H domain [M. Flynn, O. Saha, P. Young, BMC Evol. Biol. 11, 235 (2011)], which acts as a bona fide Wnt5a-responsive element. Importantly, this phospho-dependent degradation is essential for Wnt5a-Ror modulation of cell migration. Collectively, this work establishes a Wnt5a-Ror cell morphogenetic cascade involving Pdzrn3 phosphorylation and degradation.

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