Cited by 317Autophagy in Disease and TherapyParkinson's Disease Mechanisms and TreatmentsUbiquitin and proteasome pathways

TBK1 controls autophagosomal engulfment of polyubiquitinated mitochondria through p62/SQSTM1 phosphorylation

Matsumoto, Gen, Shimogori, Tomomi, Hattori, Nobutaka, Nukina, Nobuyuki·2015·Human Molecular Genetics

Abstract

Selective autophagy adaptor proteins, including p62/SQSTM1, play pivotal roles in the targeted degradation of ubiquitinated proteins or organelles through the autophagy-lysosome system. However, how autophagy adaptors promote the autophagosomal engulfment of selected substrates is poorly understood. Here, we show that p62 phosphorylation at S403 is required for the efficient autophagosomal engulfment of polyubiquitinated mitochondria during Parkin-dependent mitophagy. p62 is able to interact with Parkin-recruited mitochondria without S403 phosphorylation under mitophagy-inducing conditions, but those mitochondria are not enclosed by autophagosomes. Intriguingly, the S403 phosphorylation occurs only in the early period of mitochondrial depolarization. Optineurin and TANK-binding kinase 1 (TBK1) are transiently recruited to the polyubiquitinated mitochondria, and the activated TBK1 phosphorylates p62 at S403. TBK1 inhibitor, BX795, prevents the p62-mediated autophagosomal engulfment of Parkin-recruited mitochondria. Our results suggest that TBK1-mediated S403 phosphorylation regulates the efficient autophagosomal engulfment of ubiquitinated mitochondria as an immediate response to the mitochondrial depolarization.

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Crossref · 10.1093/hmg/ddv179

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  • TBK1 amplifies mitophagy signaling by phosphorylating OPTN and SQSTM1, enhancing their binding to ubiquitin and LC3, and promoting TBK1 autophosphorylation in a positive-feedback manner.

    “Additionally, TBK1 amplifies the signaling cascade for mitophagy by phosphorylating OPTN and SQSTM1 (which enhances binding to ubiquitin and LC3) and promoting TBK1 autophosphorylation in a positive-feedback manner [58,59].”
  • Through phosphorylation of the autophagy receptors OPTN, SQSTM1, and CALCOCO2/NDP52, TBK1 regulates macroautophagy, xenophagy and mitophagy.

    “Through its phosphorylation of the autophagy receptors OPTN, SQSTM1, and CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2) [58,59,194], TBK1 regulates several aspects of autophagy, including macroautophagy, xenophagy and mitophagy [59,90,148,194–196].”
  • Mitochondrial protein ubiquitination promotes mitochondrial recruitment of autophagy regulators and receptors such as TBK1 and optineurin.

    “Mitochondrial protein ubiquitination promotes mitochondrial recruitment of autophagy regulators and receptors such as TBK1 and optineurin (Heo et al., 2015, Matsumoto et al., 2015, Richter et al., 2016).”

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Authors
Matsumoto, G., Shimogori, T., Hattori, N., & Nukina, N.
Affiliations
  • RIKEN Center for Brain Science (JP)
  • Juntendo University (JP)
Corresponding author
  • Matsumoto, Gen
  • Nukina, Nobuyuki
Venue
Human Molecular Genetics
Published
2015-05-13
Volume
24
Issue
15
Pages
4429-4442
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
OpenAlex
W2167192779
Cited by
317
References
45
Citations by year
2026: 19 · 2025: 25 · 2024: 21 · 2023: 35 · 2022: 31 · 2021: 31 · 2020: 38 · 2019: 28 · 2018: 39 · 2017: 27 · 2016: 19 · 2015: 4
FWCI
23.26
Type
journal article
Language
en
Open access
closed
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
TBK1, p62, mitophagy, Parkin, optineurin, mitochondrial depolarization, selective autophagy, BX795, autophagy-lysosome system
MeSH terms
Sequestosome-1 Protein, Animals, Autophagy, Cell Line, Humans, Mitochondria, Phosphorylation, Protein Serine-Threonine Kinases, Mice, Knockout, Polyubiquitin, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Mice, Mitophagy

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