1. Academic Validation
  2. Proteasome inhibition promotes mono-ubiquitination and nuclear translocation of mature (52 kDa) PINK1

Proteasome inhibition promotes mono-ubiquitination and nuclear translocation of mature (52 kDa) PINK1

  • Biochem Biophys Res Commun. 2019 Sep 17;517(2):376-382. doi: 10.1016/j.bbrc.2019.07.051.
Liuke Sun 1 Hansruedi Büeler 2
Affiliations

Affiliations

  • 1 School of Life Science and Technology, Harbin Institute of Technology, 150080, Harbin, China.
  • 2 School of Life Science and Technology, Harbin Institute of Technology, 150080, Harbin, China. Electronic address: hbueler@hit.edu.cn.
Abstract

Mutations of PTEN-induced kinase 1 (PINK1) cause recessive familial Parkinson's disease. Cells lacking PINK1 display mitochondrial deficits and increased sensitivity to oxidative and proteasomal stress. It has been shown that the 52-kDa (mature) form of PINK1 in the cytoplasm mitigates proteasomal stress-induced cell death by enhancing aggresomes formation and Autophagy. Here we newly demonstrate that Proteasome dysfunction triggers mono-ubiquitination and nuclear translocation of mature PINK1. Enhancing PINK1 mono-ubiquitination by two different means increased nuclear accumulation of PINK1 independent of Proteasome inhibition. Moreover, we show that PINK1 harbors a hitherto unknown nuclear export sequence (NES) in its C-terminus. Blocking CRM1-dependent nuclear export with leptomycin B augmented PINK1 levels in the nucleus of MG132-treated cells but not in normal cells. Overall, these results show that proteasomal stress-induced mono-ubiquitination of PINK1 mediates PINK1 nuclear translocation, while PINK1 is excluded from the nucleus of healthy cells via its NES. Therefore, mature PINK1 may have a nuclear function in cells under proteasomal stress.

Keywords

Mono-ubiquitination; Nuclear translocation; PINK1; Parkinson's disease; Proteasomal stress.

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