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Cited by 25Autophagy in Disease and TherapyUbiquitin and proteasome pathwaysCellular transport and secretion

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Recruitment of autophagy initiator TAX1BP1 advances aggrephagy from cargo collection to sequestration

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Bauer, Bernd, Idinger, Jonas, Schuschnig, Martina, Ferrari, Luca, Martens, Sascha·2024·The EMBO Journal
DOI 10.1038/s44318-024-00280-5PMC PMC11611905

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Abstract

Autophagy mediates the degradation of harmful material within lysosomes. In aggrephagy, the pathway mediating the degradation of aggregated, ubiquitinated proteins, this cargo material is collected in larger condensates prior to its sequestration by autophagosomes. In this process, the autophagic cargo receptors SQSTM1/p62 and NBR1 drive cargo condensation, while TAX1BP1, which binds to NBR1, recruits the autophagy machinery to facilitate autophagosome biogenesis at the condensates. The mechanistic basis for the TAX1BP1-mediated switch from cargo collection to its sequestration is unclear. Here we show that TAX1BP1 is not a constitutive component of the condensates. Its recruitment correlates with the induction of autophagosome biogenesis. TAX1BP1 is sufficient to recruit the TBK1 kinase via the SINTBAD adapter. We define the NBR1–TAX1BP1-binding site, which is adjacent to the GABARAP/LC3 interaction site, and demonstrate that the recruitment of TAX1BP1 to cargo mimetics can be enhanced by an increased ubiquitin load. Our study suggests that autophagosome biogenesis is initiated once sufficient cargo is collected in the condensates.

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Metadata

Authors
Bauer, B., Idinger, J., Schuschnig, M., Ferrari, L., & Martens, S.
Affiliations
University of Vienna (AT)
Corresponding author
Martens, Sascha
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2024-10-24
Volume
43
Issue
23
Pages
5910-5940
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1038/s44318-024-00280-5
PMC
PMC11611905
OpenAlex
W4403703953
Cited by
25
References
2
Citations by year
2026: 16 · 2025: 9
FWCI
7.63
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Austrian Science Fund (DOI:10.55776/P30401-B21, DOI:10.55776/PAT7165623, DOI: 10.55776/W1261, DOI:10.55776/F79)
  • EC | Horizon Europe | Excellent Science | HORIZON EUROPE Marie Sklodowska-Curie Actions (847548)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
aggrephagy, TAX1BP1, autophagosome formation, NBR1, TBK1, protein aggregation, ubiquitinated proteins, p62, LC3, autophagy initiation
MeSH terms
Autophagosomes, Sequestosome-1 Protein, Autophagy, Binding Sites, HeLa Cells, Humans, Microtubule-Associated Proteins, Neoplasm Proteins, Protein Binding, Protein Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, HEK293 Cells

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