During autophagy, toxic cargo is encapsulated by autophagosomes and trafficked to lysosomes for degradation. NBR1, an autophagy receptor targeting ubiquitinated aggregates, serves as a model for studying the multivalent, heterotypic interactions of cargo-bound receptors. Here, we find that three critical NBR1 partners—ATG8-family proteins, FIP200, and TAX1BP1—each bind to distinct, overlapping determinants within a short linear interaction motif (SLiM). To explore whether overlapping SLiMs extend beyond NBR1, we analyzed >100 LC3-interacting regions (LIRs), revealing that FIP200 and/or TAX1BP1 binding to LIRs is a common phenomenon and suggesting LIRs as protein interaction hotspots. Phosphomimetic peptides demonstrate that phosphorylation generally enhances FIP200 and ATG8-family binding but not TAX1BP1, indicating differential regulation. In vivo, LIR-mediated interactions with TAX1BP1 promote optimal NBR1 flux by leveraging additional functionalities from TAX1BP1. These findings reveal a one-to-many binding modality in the LIR motif of NBR1, illustrating the cooperative mechanisms of autophagy receptors and the regulatory potential of multifunctional SLiMs.
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February 10 2025
The LC3-interacting region of NBR1 is a protein interaction hub enabling optimal flux
Brian J. North
,
Brian J. North
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Biochemistry and Cell Biology,
Geisel School of Medicine, Dartmouth College
, Hanover, NH, USA
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Amelia E. Ohnstad
,
Amelia E. Ohnstad
(Investigation, Writing - review & editing)
2Department of Physiology, Biophysics, and Systems Biology,
Weill Cornell Medicine
, New York, NY, USA
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Michael J. Ragusa
,
Michael J. Ragusa
(Formal analysis, Visualization, Writing - review & editing)
3Department of Chemistry,
Dartmouth College
, Hanover, NH, USA
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Christopher J. Shoemaker
(Conceptualization, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing)
1Department of Biochemistry and Cell Biology,
Geisel School of Medicine, Dartmouth College
, Hanover, NH, USA
Correspondence to Christopher J. Shoemaker: [email protected]
Search for other works by this author on:
Brian J. North
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Biochemistry and Cell Biology,
Geisel School of Medicine, Dartmouth College
, Hanover, NH, USA
Amelia E. Ohnstad
Investigation, Writing - review & editing
2Department of Physiology, Biophysics, and Systems Biology,
Weill Cornell Medicine
, New York, NY, USA
Michael J. Ragusa
Formal analysis, Visualization, Writing - review & editing
3Department of Chemistry,
Dartmouth College
, Hanover, NH, USA
Christopher J. Shoemaker
Conceptualization, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing
1Department of Biochemistry and Cell Biology,
Geisel School of Medicine, Dartmouth College
, Hanover, NH, USA
Correspondence to Christopher J. Shoemaker: [email protected]
Disclosures: The authors declare no competing interests exist.
Received:
July 15 2024
Revision Received:
December 05 2024
Accepted:
January 07 2025
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
National Institute of General Medical Sciences
- Award Id(s): R35GM142644,P20GM113132
Funder(s):
National Cancer Institute
- Award Id(s): P30CA023108
© 2025 North et al.
2025
North et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (4): e202407105.
Article history
Received:
July 15 2024
Revision Received:
December 05 2024
Accepted:
January 07 2025
Citation
Brian J. North, Amelia E. Ohnstad, Michael J. Ragusa, Christopher J. Shoemaker; The LC3-interacting region of NBR1 is a protein interaction hub enabling optimal flux. J Cell Biol 3 April 2025; 224 (4): e202407105. doi: https://doi.org/10.1083/jcb.202407105
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