Proteasome failure promotes positioning of lysosomes around the aggresome via local block of microtubule-dependent transport

Nava Zaarur, Anatoli B. Meriin, Eloy Bejarano, Xiaobin Xu, Vladimir L. Gabai, Ana Maria Cuervo, Michael Y. Sherman

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Ubiquitinated 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.

Original languageEnglish (US)
Pages (from-to)1336-1348
Number of pages13
JournalMolecular and Cellular Biology
Volume34
Issue number7
DOIs
StatePublished - 2014

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Proteasome Endopeptidase Complex
Lysosomes
Microtubules
Organelles
Ubiquitinated Proteins
Centrosome
Endosomes
Autophagy
Protein Transport
Protein Kinases
Small Interfering RNA
Cluster Analysis
Mitochondria
Phosphotransferases
Genome
Proteins
Protein Aggregates

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Proteasome failure promotes positioning of lysosomes around the aggresome via local block of microtubule-dependent transport. / Zaarur, Nava; Meriin, Anatoli B.; Bejarano, Eloy; Xu, Xiaobin; Gabai, Vladimir L.; Cuervo, Ana Maria; Sherman, Michael Y.

In: Molecular and Cellular Biology, Vol. 34, No. 7, 2014, p. 1336-1348.

Research output: Contribution to journalArticle

Zaarur, Nava ; Meriin, Anatoli B. ; Bejarano, Eloy ; Xu, Xiaobin ; Gabai, Vladimir L. ; Cuervo, Ana Maria ; Sherman, Michael Y. / Proteasome failure promotes positioning of lysosomes around the aggresome via local block of microtubule-dependent transport. In: Molecular and Cellular Biology. 2014 ; Vol. 34, No. 7. pp. 1336-1348.
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