p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy
Open accessAbstract
Protein degradation by basal constitutive autophagy is important to avoid accumulation of polyubiquitinated protein aggregates and development of neurodegenerative diseases. The polyubiquitin-binding protein p62/SQSTM1 is degraded by autophagy. It is found in cellular inclusion bodies together with polyubiquitinated proteins and in cytosolic protein aggregates that accumulate in various chronic, toxic, and degenerative diseases. Here we show for the first time a direct interaction between p62 and the autophagic effector proteins LC3A and -B and the related gamma-aminobutyrate receptor-associated protein and gamma-aminobutyrate receptor-associated-like proteins. The binding is mediated by a 22-residue sequence of p62 containing an evolutionarily conserved motif. To monitor the autophagic sequestration of p62- and LC3-positive bodies, we developed a novel pH-sensitive fluorescent tag consisting of a tandem fusion of the red, acid-insensitive mCherry and the acid-sensitive green fluorescent proteins. This approach revealed that p62- and LC3-positive bodies are degraded in autolysosomes. Strikingly, even rather large p62-positive inclusion bodies (2 microm diameter) become degraded by autophagy. The specific interaction between p62 and LC3, requiring the motif we have mapped, is instrumental in mediating autophagic degradation of the p62-positive bodies. We also demonstrate that the previously reported aggresome-like induced structures containing ubiquitinated proteins in cytosolic bodies are dependent on p62 for their formation. In fact, p62 bodies and these structures are indistinguishable. Taken together, our results clearly suggest that p62 is required both for the formation and the degradation of polyubiquitin-containing bodies by autophagy.
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The mCherry-GFP-LC3 reporter is designed to monitor LC3 flux because GFP signal is sensitive to acidic and/or proteolytic conditions of the lysosome lumen, whereas mCherry fluorescence persists under these environments.
“This fluorescent reporter is designed to monitor LC3 flux through the autophagy pathway because the GFP signal is sensitive to the acidic and/or proteolytic conditions of the lysosome lumen, whereas mCherry fluorescence persists under these environments.4, 17”
From Measurement of autophagy flux in the nervous system in vivo (2013) · cites this paper as [17]
Lys48-linked polyubiquitin chains signal proteasome-dependent degradation, while Lys63-linked polyubiquitin chains regulate autophagy-dependent cargo recognition by interacting with p62.
“Lys48-linked polyubiquitin chains are a signal for proteasome-dependent degradation, while Lys63-linked polyubiquitin chains play other roles, such as regulating autophagy-dependent cargo recognition by interacting with the scaffold protein p62 (also known as SQSTM1)40.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [40]
SQSTM1 mutations affecting the UBA domain impair ubiquitin recognition, whereas mutations within the LIR domain impact LC3 recognition and substrate delivery to autophagosomes.
“SQSTM1 mutations affecting the UBA domain impair ubiquitin recognition [130], whereas mutations within the LIR domain impact LC3 recognition and substrate delivery to the autophagosomes [84,131].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [84]
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Self-citation
- Authors
- Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J.-A., Outzen, H., Øvervatn, A., Bjørkøy, G., & Johansen, T.
- Affiliations
- UiT The Arctic University of Norway (NO)
- Corresponding author
- Johansen, Terje
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 282
- Issue
- 33
- Pages
- 24131-24145
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2014918593
- Cited by
- 4,578
- References
- 55
- Citations by year
- 2026: 167 · 2025: 210 · 2024: 256 · 2023: 278 · 2022: 281 · 2021: 318 · 2020: 309 · 2019: 299 · 2018: 299 · 2017: 325 · 2016: 276 · 2015: 258 · 2014: 264 · 2013: 253 · 2012: 262
- FWCI
- 73.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- p62, LC3, autophagy, aggresomes, protein degradation, autolysosomes, neurodegenerative diseases, inclusion bodies
- MeSH terms
- Sequestosome-1 Protein, Amino Acid Sequence, Autophagy, Cytosol, Fluorescent Dyes, HeLa Cells, Humans, Microtubule-Associated Proteins, Protein Binding, Transfection, Ubiquitin, RNA, Small Interfering, Multiprotein Complexes, Adaptor Proteins, Signal Transducing
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