Assembly and Regulation of CRL Ubiquitin Ligases

Wang, Kankan; Deshaies, Raymond J.; Liu, Xing

doi:10.1007/978-981-15-1025-0_3

Cited by 47 publications

(47 citation statements)

References 102 publications

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“…The most numerous ubiquitin ligases are the multi‐subunit CRLs, which are modular and can form a wide range of different enzyme complexes [24]. Within this group, a subset are the Skp‐Cullin‐F‐box ligases, which have four subunits: a RING domain protein that recruits an E2 ligase, a Cullin, a Skp protein, and an F‐box adaptor protein that binds to the substrate to be ubiquitylated.…”

Section: Expansion and Diversification Of Ubiquitin Ligases On Both Sides Of Host–pathogen Battlesmentioning

confidence: 99%

Conservation lost: host‐pathogen battles drive diversification and expansion of gene families

Lažetić

Troemel

2020

The FEBS Journal

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One of the strongest drivers in evolution is the struggle to survive a hostpathogen battle. This pressure selects for diversity among the factors directly involved in this battle, including virulence factors deployed by pathogens, their corresponding host targets, and host immune factors. A logical outcome of this diversification is that over time, the sequence of many immune factors will not be evolutionarily conserved across a broad range of species. Thus, while universal sequence conservation is often hailed as the hallmark of the importance of a particular gene, the immune system does not necessarily play by these rules when defending against coevolving pathogens. This loss of sequence conservation is in contrast to many signaling pathways in development and basic cell biology that are not targeted by pathogens. In addition to diversification, another consequence of host-pathogen battles can be an amplification in gene number, thus leading to large gene families that have sequence relatively specific to a particular strain, species, or clade. Here we highlight this general theme across a variety of pathogen virulence factors and host immune factors. We summarize the wide range and number across species of these expanded, lineage-specific host-pathogen factors including ubiquitin ligases, nucleotide-binding leucine-rich repeat receptors, GTPases, and proteins without obvious biochemical function but that nonetheless play key roles in immunity.

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Section: Expansion and Diversification Of Ubiquitin Ligases On Both Sides Of Host–pathogen Battlesmentioning

confidence: 99%

Conservation lost: host‐pathogen battles drive diversification and expansion of gene families

Lažetić

Troemel

2020

The FEBS Journal

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“…To properly maintain protein homeostasis in cells, CRLs are tightly regulated by orchestrated pathways 10–15 . Posttranslational modification of cullin proteins by NEDD8, termed cullin neddylation, represents one of the most important mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Quantitative analyses for effects of neddylation on CRL2^VHL substrate ubiquitination and degradation

2021

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Through catalyzing the ubiquitination of key regulatory proteins, cullin‐RING ubiquitin ligases (CRLs) play essential biological roles and their activities are controlled by multiple mechanisms including neddylation, the conjugation of NEDD8 to cullins. Upon neddylation, a CRL, such as the CUL1‐based CRL1, undergoes conformational changes that accelerate substrate ubiquitination. Given the structural diversity across subfamilies of CRLs and their substrates, to what extent neddylation modulates the activity of individual CRLs remains to be evaluated. Here, through reconstituting the CRL2 ubiquitination reaction in vitro, we showed that neddylation promotes CRL2VHL‐dependent degradation of both full‐length HIF1α and the degron peptide of HIF1α, resulting in more than 10‐fold increase in the rate of substrate ubiquitination. Consistently, pevonedistat (also known as MLN4924), an inhibitor of neddylation, inhibits the degradation of HIF1α in RCC4 cells stably expressing VHL in cycloheximide chase assays. However, such inhibitory effect of pevonedistat on HIF1α degradation was not observed in HEK293 cells, which was further found to be due to CRL2VHL‐independent degradation that was active in HEK293 but not RCC4 cells. After truncating HIF1α to its Carboxy‐terminal Oxygen‐Dependent Degradation (CODD) domain, we showed that pevonedistat inhibited the degradation of CODD and increased its half‐life by six‐fold in HEK293 cells. Our results demonstrate that neddylation plays a significant role in activating CRL2, and the cellular activity of CRL2VHL is better reflected by the degradation of CODD than that of HIF1α, especially under conditions where CRL2‐independent degradation of HIF1α is active.

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“…Cullin-RING ligases (CRLs) are the largest family of ubiquitin E3 ligases and are composed of modular protein subunits ( 1 ). The human genome encodes seven cullin proteins which function as scaffolding proteins and associate with a RING finger protein (RING of cullins [ROC1/RBX1 or ROC2/RBX2]) to recruit the E2 ubiquitin-conjugating enzyme ( 2 ). The N-terminal part of cullins binds to a number of specific adapter proteins that, in turn, bind to substrate receptors.…”

Section: Introductionmentioning

confidence: 99%

MEKK1-Dependent Activation of the CRL4 Complex Is Important for DNA Damage-Induced Degradation of p21 and DDB2 and Cell Survival

Bacher

Stekman

Farah

et al. 2021

Molecular and Cellular Biology

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Cullin-4 ubiquitin ligase (CRL4) complexes are differentially composed and highly dynamic protein assemblies that control many biological processes including the global genome nucleotide excision repair (GG-NER) pathway. Here we identified the kinase mitogen-activated protein kinase kinase kinase 1 (MEKK1) as a novel constitutive interactor of a cytosolic CRL4 complex that disassembles after DNA damage due to the Caspase-mediated cleavage of MEKK1. The kinase activity of MEKK1 was important to trigger auto-ubiquitination of the CRL4 complex by K48- and K63-linked ubiquitin chains. MEKK1 knockdown prohibited DNA damage-induced degradation of the CRL4 component DNA-damage binding protein 2 (DDB2) and the CRL4 substrate p21 and also cell recovery and survival. A ubiquitin replacement strategy revealed a contribution of K63-branched ubiquitin chains for DNA damage-induced DDB2/p21 decay, cell cycle regulation and cell survival. These data might have also implications for cancer, as frequently occurring mutations of MEKK1 might have an impact on genome stability and the therapeutic efficacy of CRL4-dependent immunomodulatory drugs such as thalidomide-derivatives.

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Assembly and Regulation of CRL Ubiquitin Ligases

Cited by 47 publications

References 102 publications

Conservation lost: host‐pathogen battles drive diversification and expansion of gene families

Conservation lost: host‐pathogen battles drive diversification and expansion of gene families

Quantitative analyses for effects of neddylation on CRL2^VHL substrate ubiquitination and degradation

MEKK1-Dependent Activation of the CRL4 Complex Is Important for DNA Damage-Induced Degradation of p21 and DDB2 and Cell Survival

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Assembly and Regulation of CRL Ubiquitin Ligases

Cited by 47 publications

References 102 publications

Conservation lost: host‐pathogen battles drive diversification and expansion of gene families

Conservation lost: host‐pathogen battles drive diversification and expansion of gene families

Quantitative analyses for effects of neddylation on CRL2VHL substrate ubiquitination and degradation

MEKK1-Dependent Activation of the CRL4 Complex Is Important for DNA Damage-Induced Degradation of p21 and DDB2 and Cell Survival

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Quantitative analyses for effects of neddylation on CRL2^VHL substrate ubiquitination and degradation