Proteasome failure promotes positioning of lysosomes around the aggresome via local block of microtubule-dependent transport.
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.
Department of Biochemistry, Boston University Medical School, Boston, Massachusetts, USA.
Nava
N
Zaarur
Anatoli B
AB
Meriin
Eloy
E
Bejarano
Xiaobin
X
Xu
Vladimir L
VL
Gabai
Ana Maria
AM
Cuervo
Michael Y
MY
Sherman
D000091162:AMP-Activated Protein Kinase Kinases; D001343:Autophagy; D001693:Biological Transport, Active; D018385:Centrosome / Q000378:metabolism; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C506234:USP9X protein, human; D049452:Green Fluorescent Proteins; C483047:MARK4 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex