PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity
Open accessAbstract
PINK1 kinase activates the E3 ubiquitin ligase Parkin to induce selective autophagy of damaged mitochondria. However, it has been unclear how PINK1 activates and recruits Parkin to mitochondria. Although PINK1 phosphorylates Parkin, other PINK1 substrates appear to activate Parkin, as the mutation of all serine and threonine residues conserved between Drosophila and human, including Parkin S65, did not wholly impair Parkin translocation to mitochondria. Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. In cells, the phosphomimetic ubiquitin mutant S65D bound and activated Parkin. Furthermore, expression of ubiquitin S65A, a mutant that cannot be phosphorylated by PINK1, inhibited Parkin translocation to damaged mitochondria. These results explain a feed-forward mechanism of PINK1-mediated initiation of Parkin E3 ligase activity.
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Phosphorylation of ubiquitin and PRKN at Ser65 by PINK1 is required for activation of the PINK1-PRKN pathway.
“Both events are required for the activation of the pathway.”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [5]
The Results and discussion show that ubiquitin S65 phosphorylation contributes to Parkin activation, but explicitly state that Parkin S65 phosphorylation is not required for activation by phosphomimetic ubiquitin in cells. Parkin S65A also retained ubiquitination activity, so the paper contradicts the claim that both events are required. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredPINK1 also phosphorylates ubiquitin at Ser65 (pUbS65) and PINK1-dependent phosphorylation of ubiquitin is required for translocation and activation of Parkin to initiate mitophagy.
“Recently, several groups discovered that PINK1 also phosphorylates ubiquitin at Ser65 (pUbS65) and PINK1-dependent phosphorylation of ubiquitin is required for translocation and activation of Parkin to initiate mitophagy [16–18].”
From miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1) (2016) · cites this paper as [16]
The Introduction identifies ubiquitin Ser65 as a PINK1 phosphorylation site, and the Results and discussion report that nonphosphorylatable UbS65A reduces Parkin translocation and inhibits its activation. Those findings support a role for ubiquitin phosphorylation, but the observed translocation decrease was greater than 50%, not complete; the paper does not establish the claim’s absolute requirement for translocation or directly demonstrate that this phosphorylation is required to initiate mitophagy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredUpon mitochondrial depolarization, PINK1 stabilizes on the outer mitochondrial membrane and phosphorylates ubiquitin and PRKN at Ser65.
“Upon mitochondrial depolarization, PINK1 stabilizes on the outer mitochondrial membrane, where it phosphorylates ubiquitin (Ub) and PRKN at Ser65 [5–10].”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [5]
The most extensively studied mitophagy pathway involves the E3 ligase Parkin and PINK1.
“The most extensively studied mitophagy pathway involves the E3 ligase Parkin and PINK1 (Phosphatase and tensin homolog (PTEN)-induced kinase 1) [121,122,123,124,125].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [123]
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“Recently, several groups discovered that PINK1 also phosphorylates ubiquitin at Ser65 (pUb) and PINK1-dependent phosphorylation of ubiquitin is required for translocation and activation of Parkin to initiate mitophagy [16–18].”
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- Authors
- Kane, L. A., Lazarou, M., Fogel, A. I., Li, Y., Yamano, K., Sarraf, S. A., Banerjee, S., & Youle, R. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Youle, Richard J.
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2014-04-21
- Volume
- 205
- Issue
- 2
- Pages
- 143-153
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC4003245
- OpenAlex
- W2167867141
- Cited by
- 1,298
- References
- 42
- Citations by year
- 2026: 91 · 2025: 89 · 2024: 122 · 2023: 86 · 2022: 105 · 2021: 134 · 2020: 114 · 2019: 100 · 2018: 113 · 2017: 99 · 2016: 112 · 2015: 95 · 2014: 37
- FWCI
- 74.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- PINK1, Parkin, ubiquitin phosphorylation, selective autophagy, mitophagy, mitochondrial damage
- MeSH terms
- PTEN-Induced Putative Kinase, Animals, Cell Line, Drosophila melanogaster, Enzyme Activation, Humans, Phosphorylation, Protein Kinases, Protein Structure, Tertiary, Amino Acid Substitution, Mutation, Missense, Ubiquitin, Ubiquitin-Protein Ligases
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