Insulin/IGF-1 Signaling Regulates Proteasome Activity through the Deubiquitinating Enzyme UBH-4

Matilainen, Olli; Arpalahti, Leena; Rantanen, Ville; Hautaniemi, Sampsa; Holmberg, Carina I.

doi:10.1016/j.celrep.2013.05.012

Cited by 58 publications

(105 citation statements)

References 72 publications

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“…Furthermore, the possibility of high internal recycling is supported by the observation that autophagic activity in C elegans daf-2 mutants is a prerequisite for their longevity (16,17,56). Also, increased proteasomal activity may underlie an elevated free aminoacid pool in daf-2 animals (57). However, we found that RNAi inhibition of proteasomal subunits did not lower the elevated 35 S sTCA signal in the daf-2 mutants (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Increased Protein Stability and Decreased Protein Turnover in theCaenorhabditis elegansIns/IGF-1daf-2Mutant

Depuydt

Shanmugam

Rasulova

et al. 2016

GERONA

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In Caenorhabditis elegans, cellular proteostasis is likely essential for longevity. Autophagy has been shown to be essential for lifespan extension of daf-2 insulin/IGF mutants. Therefore, it can be hypothesized that daf-2 mutants achieve this phenotype by increasing protein turnover. However, such a mechanism would exert a substantial energy cost. By using classical 35S pulse-chase labeling, we observed that protein synthesis and degradation rates are decreased in young adults of the daf-2 insulin/IGF mutants. Although reduction of protein turnover may be energetically favorable, it may lead to accumulation and aggregation of damaged proteins. As this has been shown not to be the case in daf-2 mutants, another mechanism must exist to maintain proteostasis in this strain. We observed that proteins isolated from daf-2 mutants are more soluble in acidic conditions due to increased levels of trehalose. This suggests that trehalose may decrease the potential for protein aggregation and increases proteostasis in the daf-2 mutants. We postulate that daf-2 mutants save energy by decreasing protein turnover rates and instead stabilize their proteome by trehalose.

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Section: Discussionmentioning

confidence: 99%

Increased Protein Stability and Decreased Protein Turnover in theCaenorhabditis elegansIns/IGF-1daf-2Mutant

Depuydt

Shanmugam

Rasulova

et al. 2016

GERONA

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“…Uch37 has been implicated in DNA replication and cell cycle [141], TGF-β signaling [142–145], WNT signaling via Tcf7 [146], longevity [147], cell migration and invasion [148], and the reversal of ubiquitination of proteasome subunits [138]. It is difficult to resolve common themes from the physiological studies reported to date.…”

Section: Physiological Functionmentioning

confidence: 99%

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Poot

Tian

Finley

2017

Journal of Molecular Biology

107

115

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Three deubiquitinating enzymes–Rpn11, Usp14, and Uch37–are associated with the proteasome regulatory particle. These enzymes allow proteasomes to remove ubiquitin from substrates before they are translocated into the core particle to be degraded. Although the translocation channel is too narrow for folded proteins, the force of translocation unfolds them mechanically. As translocation proceeds, ubiquitin chains bound to substrate are drawn to the channel’s entry port, where they can impede further translocation. Rpn11, situated over the port, can remove these chains without compromising degradation because substrates must be irreversibly committed to degradation before Rpn11 acts. This coupling between deubiquitination and substrate degradation is ensured by the Ins-1 loop of Rpn11, which controls ubiquitin access to its catalytic site. In contrast to Rpn11, Usp14 and Uch37 can rescue substrates from degradation by promoting substrate dissociation from the proteasome prior to the commitment step. Uch37 is unique in being a component of both the proteasome and a second multisubunit assembly, the INO80 complex. However, only recruitment into the proteasome activates Uch37. Recruitment to the proteasome likewise activates Usp14. However, the influence of Usp14 on the proteasome depends on the substrate, due to its marked preference for proteins that carry multiple ubiquitin chains. Usp14 exerts complex control over the proteasome, suppressing proteasome activity even when inactive in deubiquitination. A major challenge for the field will be to elucidate the specificities of Rpn11, Usp14, and Uch37 in greater depth, employing not only model in vitro substrates, but their endogenous targets.

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“…Decreased IIS induces proteasome activity in worms through DAF-16 transcriptional repression of the proteasome-associated deubiquitinating enzyme ubh-4 (ref. 159). UCHL5, the human orthologue of ubh-4, increases degradation of toxic proteins in mammalian cells 159 .…”

Section: Loss Of Clearance Mechanisms As a Determinant Of Ageingmentioning

confidence: 99%

“…159). UCHL5, the human orthologue of ubh-4, increases degradation of toxic proteins in mammalian cells 159 . Autophagy also contributes to the longevity phenotype of reduced IIS C. elegans mutants.…”

Section: Loss Of Clearance Mechanisms As a Determinant Of Ageingmentioning

confidence: 99%

The role of protein clearance mechanisms in organismal ageing and age-related diseases

2014

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Insulin/IGF-1 Signaling Regulates Proteasome Activity through the Deubiquitinating Enzyme UBH-4

Cited by 58 publications

References 72 publications

Increased Protein Stability and Decreased Protein Turnover in theCaenorhabditis elegansIns/IGF-1daf-2Mutant

Increased Protein Stability and Decreased Protein Turnover in theCaenorhabditis elegansIns/IGF-1daf-2Mutant

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

The role of protein clearance mechanisms in organismal ageing and age-related diseases

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