UXT chaperone prevents proteotoxicity by acting as an autophagy adaptor for p62-dependent aggrephagy

Min Ji Yoon, Boyoon Choi, Eun Jin Kim, Jiyeon Ohk, Chansik Yang, Yeon-Gil Choi, Jinyoung Lee, Chanhee Kang, Hyun Kyu Song, Yoon Ki Kim, Jae-Sung Woo, Yongcheol Cho, Eui-Ju Choi, Hosung Jung () and Chungho Kim ()
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Min Ji Yoon: Korea University
Boyoon Choi: Yonsei University College of Medicine
Eun Jin Kim: Korea University
Jiyeon Ohk: Yonsei University College of Medicine
Chansik Yang: Korea University
Yeon-Gil Choi: Korea University
Jinyoung Lee: Korea University
Chanhee Kang: Seoul National University
Hyun Kyu Song: Korea University
Yoon Ki Kim: Korea University
Jae-Sung Woo: Korea University
Yongcheol Cho: Korea University
Eui-Ju Choi: Korea University
Hosung Jung: Yonsei University College of Medicine
Chungho Kim: Korea University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract p62/SQSTM1 is known to act as a key mediator in the selective autophagy of protein aggregates, or aggrephagy, by steering ubiquitinated protein aggregates towards the autophagy pathway. Here, we use a yeast two-hybrid screen to identify the prefoldin-like chaperone UXT as an interacting protein of p62. We show that UXT can bind to protein aggregates as well as the LB domain of p62, and, possibly by forming an oligomer, increase p62 clustering for its efficient targeting to protein aggregates, thereby promoting the formation of the p62 body and clearance of its cargo via autophagy. We also find that ectopic expression of human UXT delays SOD1(A4V)-induced degeneration of motor neurons in a Xenopus model system, and that specific disruption of the interaction between UXT and p62 suppresses UXT-mediated protection. Together, these results indicate that UXT functions as an autophagy adaptor of p62-dependent aggrephagy. Furthermore, our study illustrates a cooperative relationship between molecular chaperones and the aggrephagy machinery that efficiently removes misfolded protein aggregates.

Date: 2021
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DOI: 10.1038/s41467-021-22252-7

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