Dataset Information

A conserved mechanism for the retrieval of polyubiquitinated proteins from cilia

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 quantitative proteomics, we identified that a complex of CFAP36, a conserved ciliary protein of previously unknown function, and ARL3, a small 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.

INSTRUMENT(S):

ORGANISM(S): Leishmania Tarentolae Chlamydomonas Reinhardtii Sus Scrofa Domesticus (domestic Pig)

SUBMITTER: Robyn Eisert

LAB HEAD: Alan Brown

PROVIDER: PXD062789 | Pride | 2026-06-29

REPOSITORIES: Pride

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			Action	DRS
	4522_SL_Jan2023_621_11plex_Fr1_000000200_psc20ppm.mzid	Mzid
	4524_SL_Jan2023_621_11plex_Fr2_000000201_psc20ppm.mzid	Mzid
	4526_SL_Jan2023_621_11plex_Fr3_000000202_psc20ppm.mzid	Mzid
	4528_SL_Jan2023_621_11plex_Fr4_000000203_psc20ppm.mzid	Mzid
	4530_SL_Jan2023_621_11plex_Fr5_000000204_20230202111610_psc20ppm.mzid	Mzid

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A conserved mechanism for the retrieval of polyubiquitinated proteins from cilia.

Lange Sven M SM Bennett Jeremy A JA Eisert Robyn J RJ Brown Alan A

Cell 20250820 23

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 co ...[more]

PMID: 40840444

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Project description:Study Smoking and COPD are associated with decreased mucociliary clearance and healthy smokers have shorter cilia in the large airway than nonsmokers. Intraflagellar transport (IFT) is the process by which cilia are produced and maintained. We assessed expression of IFT-related genes in smokers and nonsmokers and evaluated cilia length in the large and small airway of nonsmokers, healthy smokers, and smokers with COPD. Methods Airway epithelium was obtained via bronchoscopic brushing. Affymetrix microarrays were used to evaluate IFT gene expression in 2 independent data sets from large and small airway. Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject. Results All 40 IFT genes were expressed in the human large and small airway epithelium. In the large airway, 10 IFT genes were down-regulated and 1 up-regulated in smokers. In the small airway, 11 genes were down-regulated and 3 up-regulated in smokers. A set of 8 IFT genes was down-regulated in both data sets. In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers. Answer to the Question These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers. Strategies to normalize cilia length may be an important avenue for novel COPD therapies. Gene expression was assessed for 40 intraflagellar transport related genes in the LAE of nonsmokers (n=21) and healthy smokers (n=31) and the SAE of an independent group of nonsmokers (n=28) and healthy smokers (n=69). Cilia length was assessed in a total of 228 airway epithelium samples, including 120 LAE samples and 108 SAE samples; a subset of the 228 samples is represented among the 149 samples in this Series.