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PreprintCited by 11Genetic and Kidney Cyst DiseasesCystic Fibrosis Research AdvancesUbiquitin and proteasome pathways

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A conserved mechanism for the retrieval of polyubiquitinated proteins from cilia

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Lange, Sven M., Eisert, Robyn J., Brown, Alan·2025·Cell
DOI 10.1101/2025.04.24.650332PMC PMC12380154

Preprint — published as 10.1016/j.cell.2025.07.043 · Paper page

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Abstract

The temporospatial distribution of proteins within cilia is regulated by intraflagellar transport (IFT), wherein molecular trains shuttle between the cell body and cilium. Defects in this process impair various signal-transduction pathways and cause ciliopathies. Although K63-linked ubiquitination appears to trigger protein export from cilia, the mechanisms coupling polyubiquitinated proteins to IFT remain unclear. Using a multidisciplinary approach, we demonstrate that a complex of CFAP36, a conserved ciliary protein of previously unknown function, and ARL3, a GTPase involved in ciliary import, binds polyubiquitinated proteins and links them to retrograde IFT trains. CFAP36 uses a coincidence detection mechanism to simultaneously bind two IFT subunits accessible only in retrograde trains. Depleting CFAP36 accumulates K63-linked ubiquitin in cilia and disrupts Hedgehog signaling, a pathway reliant on the retrieval of ubiquitinated receptors. These findings advance our understanding of ubiquitin-mediated protein transport and ciliary homeostasis, and demonstrate how structural changes in IFT trains achieve cargo selectivity.

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Metadata

Authors
Lange, S. M., Eisert, R. J., & Brown, A.
Affiliations
Harvard University (US)
Corresponding author
Brown, Alan
ORCID
Venue
Cell
Publisher
openRxiv
Published
2025-04-26
Volume
188
Issue
23
Pages
6492-6508.e18
ISSN
0092-8674 (ISSN-L)
DOI
10.1101/2025.04.24.650332
PMC
PMC12380154
OpenAlex
W4413385180
Cited by
11
References
1
Citations by year
2026: 7 · 2025: 4
FWCI
6.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
Funders
  • Richard and Susan Smith Family Foundation
  • Sara Elizabeth O'Brien Trust
  • National Institute of General Medical Sciences (R01GM143183, R01GM141109)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
cilia, intraflagellar transport, K63-linked ubiquitination, polyubiquitinated proteins, ARL3, GTPase, coincidence detection, Hedgehog signaling, ciliopathies
MeSH terms
Animals, Cilia, Humans, Signal Transduction, ADP-Ribosylation Factors, Protein Transport, Ubiquitin, Mice, Hedgehog Proteins, Ubiquitination

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