K27-linked noncanonic ubiquitination in immune regulation

Zhou, Qingqing; Zhang, Jun

doi:10.1002/jlb.4ru0620-397rr

Cited by 14 publications

(16 citation statements)

References 110 publications

(212 reference statements)

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“…K27-linked ubiquitination plays an important role in the innate immune response and T cell signaling 37 . Many E3 Ub ligases have been reported to catalyze K27-linked ubiquitination, including RNF185 38 , membrane-associated RING-CH-type 8 (MARCH8) 39 , and TRIM25 40 .…”

Section: Resultsmentioning

confidence: 99%

RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy

et al. 2022

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Virus infection affects cellular proteostasis and provides an opportunity to study this cellular process under perturbation. The proteostasis network in the endoplasmic reticulum (ER) is composed of the calnexin cycle, and the two protein degradation pathways ER-associated protein degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD/ER-phagy/reticulophagy). Here we show that calnexin and calreticulin trigger Zaire Ebolavirus (EBOV) glycoprotein GP1,2 misfolding. Misfolded EBOV-GP1,2 is targeted by ERAD machinery, but this results in lysosomal instead of proteasomal degradation. Moreover, the ER Ub ligase RNF185, usually associated with ERAD, polyubiquitinates EBOV-GP1,2 on lysine 673 via ubiquitin K27-linkage. Polyubiquinated GP1,2 is subsequently recruited into autophagosomes by the soluble autophagy receptor sequestosome 1 (SQSTM1/p62), in an ATG3- and ATG5-dependent manner. We conclude that EBOV hijacks all three proteostasis mechanisms in the ER to downregulate GP1,2 via polyubiquitination and show that this increases viral fitness. This study identifies linkages among proteostasis network components previously thought to function independently.

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Section: Resultsmentioning

confidence: 99%

RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy

et al. 2022

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“…[43], STING [44], IRF3 and IRF7 [45], among others [46,47]. Similarly, K33-chains are recognised in the turnover of RAS GTPases [48], glycine decarboxylase [49], and 3-hydroxy-3-methylglutaryl CoA reductase [49].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, like K48-chains, K27-chains are important facilitators of substrate processing by proteasomes [39]. K27- and K29-chains destabilise several key innate immune proteins, including NLRP3 [40], MDA5 and RIGI [41, 42], ULK1 [43], STING [44], IRF3 and IRF7 [45], among others [46, 47]. Similarly, K33-chains are recognised in the turnover of RAS GTPases [48], glycine decarboxylase [49], and 3-hydroxy-3-methylglutaryl CoA reductase [49].…”

Section: Discussionmentioning

confidence: 99%

IL-1β turnover by TRIP12 and AREL1 ubiquitin ligases and UBE2L3 limits inflammation

Mishra

Crespo-Puig

McCarthy

et al. 2022

Preprint

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The cytokine interleukin-1β (IL-1β) has pivotal roles in antimicrobial immunity, but also incites inflammatory pathology. Bioactive IL-1β is released following proteolytic maturation of the pro-IL-1β precursor by caspase-1 inflammasomes. UBE2L3/UBCH7, a conserved ubiquitin conjugating enzyme, promotes pro-IL-1β ubiquitylation and proteasomal disposal. However, UBE2L3 actions in vivo and ubiquitin ligases involved in this process are unknown. Here we report that deletion of Ube2l3 in mice markedly reduces pro-IL-1β turnover in macrophages, leading to excessive mature IL-1β production, neutrophilic inflammation and disease symptoms following inflammasome activation. A family-wide siRNA screen identified two ubiquitin ligases, TRIP12 and AREL1, which we show add K27-, K29-and K33-poly-ubiquitin chains on lysine residues in the 'pro' domain and destabilise pro-IL-1β. Mutation of ubiquitylation sites increased pro-IL-1β stability, but did not affect proteolysis by caspase-1. The extent of mature IL-1β production is therefore determined by precursor abundance, and UBE2L3, TRIP12 and AREL1 limit inflammation by shrinking the cellular pool of pro-IL-1β. Our study has uncovered fundamental processes governing IL-1β homeostasis and provided molecular insights that could be exploited to mitigate its adverse actions in disease.'floxed' Ube2l3 exon 1 (Ube2l3 fx/fx mice) were crossed with Csf1r-cre/Esr1 mice that express the Cre recombinase-oestrogen receptor fusion protein whose activity is induced by 4-.

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“…Homotypic polyubiquitination is mediated by the N-terminal methionine (M1) or seven Lys residues (K6, K11, K27, K29, K33, K48, K63) of ubiquitin, and each polyubiquitination linkage type has a distinctive conformation and a unique role [ 32 ]. Among the homotypic polyubiquitin chains, K48- and K63-linked ubiquitin chains, which are referred to as canonic polyubiquitin chains, exert several functions, such as proteasomal degradation and signal transduction.…”

Section: Discussionmentioning

confidence: 99%

AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination

Baek

Jang

2021

IJMS

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Activating molecule in Beclin-1-regulated autophagy (AMBRA1), a negative regulator of tumorigenesis, is a substrate receptor of the ubiquitin conjugation system. ALDH1B1, an aldehyde dehydrogenase, is a cancer stem cell (CSC) marker that is required for carcinogenesis via upregulation of the β-catenin pathway. Although accumulating evidence suggests a role for ubiquitination in the regulation of CSC markers, the ubiquitination-mediated regulation of ALDH1B1 has not been unraveled. While proteome analysis has suggested that AMBRA1 and ALDH1B1 can interact, their interaction has not been validated. Here, we show that AMBRA1 is a negative regulator of ALDH1B1. The expression of ALDH1B1-regulated genes, including PTEN, CTNNB1 (β-catenin), and CSC-related β-catenin target genes, is inversely regulated by AMBRA1, suggesting a negative regulatory role of AMBRA1 in the expression of ALDH1B1-regulated genes. We found that the K27- and K33-linked ubiquitination of ALDH1B1 is mediated via the cooperation of AMBRA1 with other E3 ligases, such as TRAF6. Importantly, ubiquitination site mapping revealed that K506, K511, and K515 are important for the K27-linked ubiquitination of ALDH1B1, while K33-linked ubiquitination occurs at K506. A ubiquitination-defective mutant of ALDH1B1 increased the self-association ability of ALDH1B1, suggesting a negative correlation between the ubiquitination and self-association of ALDH1B1. Together, our findings indicate that ALDH1B1 is negatively regulated by AMBRA1-mediated noncanonical ubiquitination.

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K27-linked noncanonic ubiquitination in immune regulation

Cited by 14 publications

References 110 publications

RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy

RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy

IL-1β turnover by TRIP12 and AREL1 ubiquitin ligases and UBE2L3 limits inflammation

AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination

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