A dimer-monomer switch controls CHIP-dependent substrate ubiquitylation and processing

Balaji, Vishnu; Müller, Leonie; Lorenz, Robin; Kevei, Éva; Zhang, William; Santiago, Ulises; Gebauer, Jan; Llamas, Ernesto; Camacho, Carlos J.; Pokrzywa, Wojciech; Hoppe, Thorsten

doi:10.1016/j.molcel.2022.08.003

Cited by 12 publications

(7 citation statements)

References 70 publications

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“…A recent study identified UFD‐2 as an E3 that binds to CHN‐1(homologue of STUB1) and promotes CHN‐1 autoubiquitination activity with implications in lipid metabolism [28]. Furthermore, it is proposed that the dynamic monomeric/dimeric nature of STUB1 is influenced by its ubiquitination status [29]. These results suggest that STUB1 biology is greatly influenced by its ubiquitination status with implication in pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono‐ubiquitination

2023

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The development of neurological pathologies is linked to the accumulation of protein aggregates like alpha‐synuclein in Parkinson's disease and tau protein in Alzheimer's disease. Mono‐ or di‐ubiquitination of these molecules has been reported to stabilize aggregates and contribute to the disorders. STIP1 Homologous and U‐Box‐containing protein 1 (STUB1) is a multifunctional protein that maintains proteostasis and insulin signalling. In spinocerebellar ataxia 16 (SCAR16), an autosomal recessive neurodegenerative disease, mutations in and aggregation of STUB1 are reported. Despite the well‐accepted neuroprotective role of STUB1, very little is known of regulatory mechanisms that control the dynamics of STUB1 aggregate assembly. Here, we report that CARP2, a ubiquitin ligase, is a novel regulator of STUB1. CARP2 interacts and mono‐ubiquitinates STUB1. Furthermore, we found that CARP2 regulates STUB1 through its TPR motif, a domain that is also associated with HSP70. Modification of STUB1 by CARP2 leads to detergent‐insoluble aggregate formation. Importantly, pathogenic mutants of STUB1 are more prone than the wild‐type to CARP2‐mediated aggregate assembly. Hence our findings revealed CARPs (CARP1 & CARP2) as novel regulators of STUB1 and controlled its cytosolic versus aggregate dynamics.

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Section: Discussionmentioning

confidence: 99%

CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono‐ubiquitination

2023

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“…Thus, monoubiquitination of CHIC2, and potentially nearby substrates, could be involved in regulation of receptor trafficking. Monoubiquitination of CHIP itself has also been recently shown to change its oligomeric state and processivity 41 , so modulation of CHIP's autoubiquitination activity by CHIC2 might also be a contributing factor. Finally, it is also possible that CHIC2 may simply serve to inhibit CHIP's chaperone-dependent activity in specific, membrane-proximal regions, thus protecting some substrates from degradation.…”

Section: Discussionmentioning

confidence: 99%

Interaction with the membrane-anchored protein CHIC2 constrains the ubiquitin ligase activity of CHIP

Callahan

Hodul

Carroll

et al. 2023

Preprint

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Maintenance of cellular health requires the proper regulation of E3 ubiquitin ligases. The E3 ligase CHIP is canonically regulated by its interactions with the molecular chaperones Hsp70 and Hsp90, which focus CHIP's ubiquitination activity on misfolded proteins. Here, we report a chaperone-independent interaction of CHIP with the membrane-anchored protein CHIC2, which strongly attenuates CHIP's ligase activity. We show that CHIC2 outcompetes abundant, cytosolic chaperones through its exquisite CHIP selectivity, rather than through enhanced affinity. In proteomic experiments, we find that CHIC2 knockout phenocopies CHIP knockout in certain cell types, implying that chaperone-independent interactions can sometimes predominate CHIP's functions. Furthermore, loss of the CHIP-CHIC2 interaction induces neurodegeneration and shortens lifespan in C. elegans, demonstrating that formation of this chaperone-independent complex is important in animals. We propose that CHIC2 attenuates CHIP activity at the membrane, offering a novel mechanism by which this ubiquitin ligase can be regulated.

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“…We have recently used the same cross-linking protocol for mouse embryonic fibroblasts and HeLa cells, for CHIP overexpression studies, and for recombinant CHIP proteins. 1 …”

Section: Before You Beginmentioning

confidence: 99%

“…Furthermore, to further confirm the running behavior of the monomer counterpart of the protein CHIP, we have generated a mutant that cannot self-assemble (CHIP(L165R)) due to a point mutation in its dimerization interphase. 1 …”

Section: Limitationsmentioning

confidence: 99%

Chemical cross-linking to study protein self-assembly in cellulo

Müller,

Salman,

Hoppe

2024

STAR Protocols

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A dimer-monomer switch controls CHIP-dependent substrate ubiquitylation and processing

Cited by 12 publications

References 70 publications

CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono‐ubiquitination

CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono‐ubiquitination

Interaction with the membrane-anchored protein CHIC2 constrains the ubiquitin ligase activity of CHIP

Chemical cross-linking to study protein self-assembly in cellulo

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