Cytosolic PINK1 orchestrates protein translation during proteasomal stress by phosphorylating the translation elongation factor eEF1A1

Siyue Qin; Ling Ye; Youshi Zheng; Ju Gao

doi:10.1002/1873-3468.14030

Cytosolic PINK1 orchestrates protein translation during proteasomal stress by phosphorylating the translation elongation factor eEF1A1

FEBS Lett. 2021 Feb;595(4):507-520. doi: 10.1002/1873-3468.14030. Epub 2021 Jan 6.

Authors

Siyue Qin¹, Ling Ye², Youshi Zheng³, Ju Gao³

Affiliations

¹ Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, China.
² Lishui Center for Disease Control and Prevention, Lishui, China.
³ The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.

PMID: 33354788
DOI: 10.1002/1873-3468.14030

Abstract

Mutations in PINK1 (PTEN-induced putative kinase 1) are associated with autosomal recessive early-onset Parkinson's disease. Full-length PINK1 (PINK1-l) has been extensively studied in mitophagy; however, the functions of the short form of PINK1 (PINK1-s) remain poorly understood. Here, we report that PINK1-s is recruited to ribosome fractions after short-term inhibition of proteasomes. The expression of PINK1-s greatly inhibits protein synthesis even without proteasomal stress. Mechanistically, PINK1-s phosphorylates the translation elongation factor eEF1A1 during proteasome inhibition. The expression of the phosphorylation mimic mutation eEF1A1S396E rescues protein synthesis defects and cell viability caused by PINK1 knockout. These findings implicate an important role for PINK1-s in protecting cells against proteasome stress through inhibiting protein synthesis.

Keywords: PINK1; Phosphorylation; Proteasome inhibition; Protein synthesis; Stress response; eEF1A1.

MeSH terms

Amino Acid Sequence
Anisomycin / pharmacology
Cell Line
Cell Survival / drug effects
Cysteine Proteinase Inhibitors / pharmacology
Epithelial Cells
HEK293 Cells
Humans
Leupeptins / pharmacology
Peptide Elongation Factor 1 / genetics*
Peptide Elongation Factor 1 / metabolism
Phosphorylation / drug effects
Proteasome Endopeptidase Complex / drug effects*
Proteasome Endopeptidase Complex / metabolism
Protein Biosynthesis / drug effects*
Protein Kinases / genetics*
Protein Kinases / metabolism
Protein Processing, Post-Translational*
Protein Synthesis Inhibitors / pharmacology
Proteolysis / drug effects
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Ribosomes / drug effects
Ribosomes / genetics
Ribosomes / metabolism

Substances

Cysteine Proteinase Inhibitors
EEF1A1 protein, human
Leupeptins
Peptide Elongation Factor 1
Protein Synthesis Inhibitors
RNA, Small Interfering
Anisomycin
Protein Kinases
PTEN-induced putative kinase
Proteasome Endopeptidase Complex
benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Grants and funding

31600616/National Natural Science Foundation of China