K27‐linked ubiquitylation promotes p97 substrate processing and is essential for cell proliferation

Shearer, Robert F.; Typas, Dimitris; Coscia, Fabian; Schovsbo, Sofie; Kruse, Thomas; Mund, Andreas; Mailand, Niels

doi:10.15252/embj.2021110145

Cited by 15 publications

(13 citation statements)

References 54 publications

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“…Similar to Gp78 (Morito et al, 2008), HERC3 may function as an E4 enzyme that elongates the Ub chains initiated by RNF5/185, as it directly binds to Ub (Cruz et al, 2001). Alternatively, HERC3 may modify the Ub chains initiated by RNF5/185 by adding non-canonical Ub chains, such as K27 chains, which promote the p97-proteasome pathway (Shearer et al, 2022), as HERC3 has been shown to promote K27-linked polyubiquitination (Zhang et al, 2022a).…”

Section: Discussionmentioning

confidence: 99%

HERC3 E3 ligase provides an ERAD branch eliminating select membrane proteins

Kamada,

Ohnishi,

Nakashima

et al. 2023

Preprint

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Aberrant proteins located in the endoplasmic reticulum (ER) undergo rapid ubiquitination by multiple ubiquitin (Ub) E3 ligases and are retrotranslocated to the cytosol as part of the ER-associated degradation (ERAD). Despite several ERAD branches involving different Ub E3 ligases, each with distinct substrate specificity, the molecular machinery responsible for these ERAD branches in mammalian cells remains not fully understood. In this study, we have discovered a cytosolic Ub ligase called HERC3, which fulfills a distinct role in facilitating the ERAD of select polytopic membrane proteins. Using a series of multiplex knockdown/knockout experiments, we have demonstrated that HERC3 functions independently of the ER-embedded ubiquitin ligases RNF5 and RNF185 (RNF5/185) to facilitate the ubiquitination, retrotranslocation, and ERAD of misfolded CFTR. Furthermore, HERC3 collaborates with RNF5/185 to enhance the association of UBQLN proteins, thereby augmenting the retrotranslocation and ERAD of misfolded CFTR. While RNF5/185 participates in the ERAD process of both misfolded ABCB1 and CFTR, HERC3 specifically promotes the ERAD of CFTR, likely due to its ability to interact with the less hydrophobic membrane-spanning domains of CFTR. HERC3 may detect exposed transmembrane domains on the cytoplasmic surface of the ER, thereby facilitating the recruitment of UBQLN and subsequently accelerating the ERAD of select polytopic membrane proteins.

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Section: Discussionmentioning

confidence: 99%

HERC3 E3 ligase provides an ERAD branch eliminating select membrane proteins

Kamada,

Ohnishi,

Nakashima

et al. 2023

Preprint

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“…K27-, K29- and K33-poly-ubiquitin chain types are associated with proteasomal degradation of several proteins. 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].…”

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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“…Non-proteolytic roles for polyubiquitination include, for K6 linkages, mitochondrial homeostasis ( Durcan et al, 2014 ) and the DNA damage response ( Wu-Baer et al, 2003 ; Elia et al, 2015 ; Blount et al, 2020 ), and for K27 linkages, cellular proliferation ( Shearer et al, 2022 ) and the innate immune response ( Yin et al, 2019 ). K29 polyubiquitin linkages play a role in the cellular stress response and in regulating the cell cycle ( Yu et al, 2021 ) while K33-linked chains are involved in T cell activation and signaling ( Huang et al, 2010 ; Yang et al, 2015 ).…”

Section: The Ubiquitin-proteasome Systemmentioning

confidence: 99%

The role of ubiquitination in spinal and bulbar muscular atrophy

Sengupta

Pluciennik²,

Merry³

2022

Front. Mol. Neurosci.

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Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative and neuromuscular genetic disease caused by the expansion of a polyglutamine-encoding CAG tract in the androgen receptor (AR) gene. The AR is an important transcriptional regulator of the nuclear hormone receptor superfamily; its levels are regulated in many ways including by ubiquitin-dependent degradation. Ubiquitination is a post-translational modification (PTM) which plays a key role in both AR transcriptional activity and its degradation. Moreover, the ubiquitin-proteasome system (UPS) is a fundamental component of cellular functioning and has been implicated in diseases of protein misfolding and aggregation, including polyglutamine (polyQ) repeat expansion diseases such as Huntington’s disease and SBMA. In this review, we discuss the details of the UPS system, its functions and regulation, and the role of AR ubiquitination and UPS components in SBMA. We also discuss aspects of the UPS that may be manipulated for therapeutic effect in SBMA.

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K27‐linked ubiquitylation promotes p97 substrate processing and is essential for cell proliferation

Cited by 15 publications

References 54 publications

HERC3 E3 ligase provides an ERAD branch eliminating select membrane proteins

HERC3 E3 ligase provides an ERAD branch eliminating select membrane proteins

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

The role of ubiquitination in spinal and bulbar muscular atrophy

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