Choi, Won Hoon Yun, Yejin Park, Seoyoung Jeon, Jun Hyoung Lee, Jeeyoung Lee, Jung Hoon Yang, Su-A Kim, Nak-Kyoon Jung, Chan Hoon Kwon, Yong Tae Han, Dohyun Lim, Sang Min Lee, Min Jae 2024-01-19T17:01:07Z 2024-01-19T17:01:07Z 2021-09-02 2020-08-11 0027-8424 https://pubs.kist.re.kr/handle/201004/118262 The 26S proteasome, a self-compartmentalized protease complex, plays a crucial role in protein quality control. Multiple levels of regulatory systems modulate proteasomal activity for substrate hydrolysis. However, the destruction mechanism of mammalian proteasomes is poorly understood. We found that inhibited proteasomes are sequestered into the insoluble aggresome via HDAC6- and dynein-mediated transport. These proteasomes colocalized with the autophagic receptor SQSTM1 and cleared through selective macroautophagy, linking aggresomal segregation to autophagic degradation. This proteaphagic pathway was counterbalanced with the recovery of proteasomal activity and was critical for reducing cellular proteasomal stress. Changes in associated proteins and polyubiquitylation on inhibited 26S proteasomes participated in the targeting mechanism to the aggresome and autophagosome. The STUB1 E3 Ub ligase specifically ubiquitylated purified human proteasomes in vitro, mainly via Lys63-linked chains. Genetic and chemical inhibition of STUB1 activity significantly impaired proteasome processing and reduced resistance to proteasomal stress. These data demonstrate that aggresomal sequestration is the crucial upstream event for proteasome quality control and overall protein homeostasis in mammals. English NATL ACAD SCIENCES 26S PROTEASOMES STORAGE GRANULES UBIQUITIN AUTOPHAGY DEGRADATION COMPLEXES REVEALS PATHWAY SITES HSP42 Aggresomal sequestration and STUB1-mediated ubiquitylation during mammalian proteaphagy of inhibited proteasomes Article 10.1073/pnas.1920327117 1 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.117, no.32, pp.19190 - 19200 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 117 32 19190 19200 scie scopus 000562378600015 2-s2.0-85089614027 Multidisciplinary Sciences Science & Technology - Other Topics Article 26S PROTEASOMES STORAGE GRANULES UBIQUITIN AUTOPHAGY DEGRADATION COMPLEXES REVEALS PATHWAY SITES HSP42 proteasome aggresome proteaphagy ubiquitin STUB1