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

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.

GeneSetR: A web server for gene set analysis based on genome-wide Perturb-Seq data

“…This gene encodes eEF1A1, one of the most abundant proteins in the cell, which is involved in the elongation phase of protein synthesis, facilitating the delivery of aminoacyl-tRNAs to the ribosome (30). However, eEF1A1 is not only a translation factor, but also exhibits chaperone-like activity and participates in cellular responses to various stresses, including heat-shock, proteasomal stress, and ER stress (30)(31)(32). Moreover, eEF1A1 has been reported to inhibit Gcn2-mediated eIF2α phosphorylation; thus, its decreased expression could also positively regulate ATF4 signaling (30).…”

Intersections of Ubiquitin-Proteosome System and Autophagy in Promoting Growth of Glioblastoma Multiforme: Challenges and Opportunities

“…PINK1 is translated in the cytoplasm and transported across the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), where it is cleaved by mitochondrial processing peptidase (MPP) and presenilin-associated rhomboid-like protease (PARL), and subsequently returned to the cytoplasm where, under normal conditions, it is either degraded by the proteasome or stabilized by a chaperone protein, exerting an inhibitory effect on mitophagy through interactions with Parkin (an ubiquitin E3 ligase that mono-ubiquitinates and poly-ubiquitinates proteins) and protein kinase A (PKA) [ 145 ]. There is also evidence that cytosolic PINK1 acts as a sensor of the UPS stress as its accumulation upon proteasome inhibition results in the PINK1-dependent phosphorylation of the translation elongation factor, known as the eukaryotic translation elongation factor 1 alpha 1 (eEF1A1), leading to decreased translational activity [ 146 ]. Upon mitochondrial damage or dysfunction, the mitochondrial membrane potential is decreased, causing PINK1 to remain on the OMM where it is dimerized and becomes phosphorylated [ 147 ].…”

The Role of Mitophagy in Regulating Cell Death

“…Due to PINK1's ability to rapidly accumulate on the OMM and activate in response to mitochondrial stressors, it has been suggested that PINK1 functions as a sensor to probe for damaged mitochondria [ 31 , 32 ]. Recently, it was also reported that PINK1-s (a short form of PINK1), as a sensor of proteasomal activities, protected cells against proteasome stress through inhibiting protein synthesis [ 33 , 34 ]. Subsequent homodimerization of PINK1 on the OMM leads to autophosphorylation, which promotes kinase activation and facilitates the translocation of Parkin to the membrane of damaged mitochondria and recruitment of substrates ubiquitin to the mitochondria [ 13 , 27 , 35 ].…”