Emerging roles of deubiquitinases in cancer‐associated pathways

Sacco, Joseph J.; Coulson, Judy M.; Clague, Michael J.; Urbé, Sylvie

doi:10.1002/iub.300

Cited by 156 publications

(163 citation statements)

References 170 publications

(138 reference statements)

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“…These two kinases are normally ubiquitinated by K33 and K29 chains (42). STK11 cannot phosphorylate and activate them unless the ubiquitin chains are removed by the deubiquitinating enzyme Usp9x (43,44). Therefore, activities of both STK11 and Usp9x are necessary for activation of MARK4 and NUAK1.…”

Section: Resultsmentioning

confidence: 99%

Proteasome Failure Promotes Positioning of Lysosomes around the Aggresome via Local Block of Microtubule-Dependent Transport

Zaarur

Meriin

Bejarano

et al. 2014

Molecular and Cellular Biology

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bUbiquitinated proteins aggregate upon proteasome failure, and the aggregates are transported to the aggresome. In aggresomes, protein aggregates are actively degraded by the autophagy-lysosome pathway, but why targeting the aggresome promotes degradation of aggregated species is currently unknown. Here we report that the important factor in this process is clustering of lysosomes around the aggresome via a novel mechanism. Proteasome inhibition causes formation of a zone around the centrosome where microtubular transport of lysosomes is suppressed, resulting in their entrapment and accumulation. Microtubule-dependent transport of other organelles, including autophagosomes, mitochondria, and endosomes, is also blocked in this entrapment zone (E-zone), while movement of organelles at the cell periphery remains unaffected. Following the whole-genome small interfering RNA (siRNA) screen for proteins involved in aggresome formation, we defined the pathway that regulates formation of the E-zone, including the Stk11 protein kinase, the Usp9x deubiquitinating enzyme, and their substrate kinase MARK4. Therefore, upon proteasome failure, targeting of aggregated proteins of the aggresome is coordinated with lysosome positioning around this body to facilitate degradation of the abnormal species.

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Section: Resultsmentioning

confidence: 99%

Proteasome Failure Promotes Positioning of Lysosomes around the Aggresome via Local Block of Microtubule-Dependent Transport

Zaarur

Meriin

Bejarano

et al. 2014

Molecular and Cellular Biology

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“…115 CYLD is also involved in the regulation of other cellular processes, such as cell migration and spermatogenesis. 116 Though not a therapeutic target due to its tumor suppressor status, a better understanding of CYLD regulation may be of value in developing strategies to reactivate its expression, and/or lead to its use as a biomarker for prognostic or therapeutic use related to the activity of the NFκB pathway in various cancers.…”

Section: Cyldmentioning

confidence: 99%

Ubiquitin becomes ubiquitous in cancer

Shi

Grossman

2010

Cancer Biology & Therapy

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“…A number of deubiquitinases are reported to play critical roles in diverse cellular and physiological functions such as cell signaling, histone modification and so on [35,36]. Abnormal deubiquitinase activity is closely related to tumor cell survival as these enzymes modulate TGF-β, Wnt and TNF signaling pathways [37]. Several small molecules that inhibit distinct deubiquitinases have been identified, and these small molecules would be useful tools for studying the molecular mechanisms underlying the actions of these deubiquitinases, in addition to their potential therapeutic applications [38,39].…”

Section: Introductionmentioning

confidence: 99%

A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30

et al. 2014

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Mitochondrial fusion is a highly coordinated process that mixes and unifies the mitochondrial compartment for normal mitochondrial functions and mitochondrial DNA inheritance. Dysregulated mitochondrial fusion causes mitochondrial fragmentation, abnormal mitochondrial physiology and inheritance, and has been causally linked with a number of neuronal diseases. Here, we identified a diterpenoid derivative 15-oxospiramilactone (S3) that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfn1 or Mfn2. A mitochondria-localized deubiquitinase USP30 is a target of S3. The inhibition of USP30 by S3 leads to an increase of non-degradative ubiquitination of Mfn1/2, which enhances Mfn1 and Mfn2 activity and promotes mitochondrial fusion. Thus, through the use of an inhibitor of USP30, our study uncovers an unconventional function of non-degradative ubiquitination of Mfns in promoting mitochondrial fusion.

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Emerging roles of deubiquitinases in cancer‐associated pathways

Cited by 156 publications

References 170 publications

Proteasome Failure Promotes Positioning of Lysosomes around the Aggresome via Local Block of Microtubule-Dependent Transport

Proteasome Failure Promotes Positioning of Lysosomes around the Aggresome via Local Block of Microtubule-Dependent Transport

Ubiquitin becomes ubiquitous in cancer

A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30

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