Autophagy promotes primary ciliogenesis by removing ofd1 from centriolar satellites

ABSTRACT The primary cilium is a microtubule-based organelle that functions in sensory and signalling pathways. Defects in ciliogenesis can lead to a group of genetic syndromes known as

ciliopathies1,2,3. However, the regulatory mechanisms of primary ciliogenesis in normal and cancer cells are incompletely understood. Here we demonstrate that autophagic degradation of a

ciliopathy protein, OFD1 (oral-facial-digital syndrome 1), at centriolar satellites promotes primary cilium biogenesis. Autophagy is a catabolic pathway in which cytosol, damaged organelles

and protein aggregates are engulfed in autophagosomes and delivered to lysosomes for destruction4. We show that the population of OFD1 at the centriolar satellites is rapidly degraded by

autophagy upon serum starvation. In autophagy-deficient _Atg5_ or _Atg3_ null mouse embryonic fibroblasts, OFD1 accumulates at centriolar satellites, leading to fewer and shorter primary

cilia and a defective recruitment of BBS4 (Bardet–Biedl syndrome 4) to cilia. These defects are fully rescued by OFD1 partial knockdown that reduces the population of OFD1 at centriolar

satellites. More strikingly, OFD1 depletion at centriolar satellites promotes cilia formation in both cycling cells and transformed breast cancer MCF7 cells that normally do not form cilia.

This work reveals that removal of OFD1 by autophagy at centriolar satellites represents a general mechanism to promote ciliogenesis in mammalian cells. These findings define a newly

recognized role of autophagy in organelle biogenesis. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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APOPTOSIS Article Open access 15 December 2023 NUDCL2 IS AN AUTOPHAGY RECEPTOR THAT MEDIATES SELECTIVE AUTOPHAGIC DEGRADATION OF CP110 AT MOTHER CENTRIOLES TO PROMOTE CILIOGENESIS Article

Open access 03 September 2021 A CLASS I PI3K SIGNALLING NETWORK REGULATES PRIMARY CILIA DISASSEMBLY IN NORMAL PHYSIOLOGY AND DISEASE Article Open access 21 August 2024 REFERENCES * Sang, L.

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Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank D. Moughon and W. Fan for initial purification of LC3 complex; N. Mizushima for _Atg5_+/+ and _Atg5__−/−_ MEFs and

M. Komatsu for _Atg3_+/+ and _Atg3__−/−_ MEFs; H. Zhou for helpful discussions and quantitative RT–PCR data analysis; A. Kodani and J. F. Reiter for reagents, helpful discussions and

technical assistance; and B. Levine for helpful discussions and critical reading of the manuscript. The electron microscopy studies were performed by C. Miller and V. Gattone II at the

Indiana University School of Medicine Electron Microscopy Center that is supported by the Polycystic Kidney Disease Foundation. This work was supported by grants from the American Cancer

Society (RSG-11-274-01-CCG) and National Cancer Institute (CA133228) to Q.Z. and grants from the Italian Telethon Foundation (TGM11CB3) and the EU FP7/2007-2013 Programme (Syscilia grant

agreement no. 241955) to B.F. The work was partially supported by China Scholarship Council to Z.T. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Internal Medicine, Center for

Autophagy Research, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA Zaiming Tang & Qing Zhong * Department of Biochemistry, University of Texas Southwestern

Medical Center, Dallas, 75390, Texas, USA Zaiming Tang & Qing Zhong * Division of Biochemistry, Department of Molecular and Cell Biology, Biophysics and Structural Biology, University of

California, Berkeley, 94720, California, USA Zaiming Tang, Mary Grace Lin & Qing Zhong * State Key Laboratory of Plant Physiology and Biochemistry, College of Life Sciences, Zhejiang

University, Hangzhou, 310058, China Zaiming Tang & Muyuan Zhu * Department of Biology, Stanford University, Stanford, 94305, California, USA Timothy Richard Stowe & Tim Stearns *

National Institute of Biological Sciences, Beijing, 102206, China She Chen * Department of Translational Medical Sciences, Medical Genetics Services, Federico II University, Via Pietro

Castellino 111, Naples, Italy, Brunella Franco * Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino 111, Naples, Italy, Brunella Franco Authors * Zaiming Tang View

author publications You can also search for this author inPubMed Google Scholar * Mary Grace Lin View author publications You can also search for this author inPubMed Google Scholar *

Timothy Richard Stowe View author publications You can also search for this author inPubMed Google Scholar * She Chen View author publications You can also search for this author inPubMed 

Google Scholar * Muyuan Zhu View author publications You can also search for this author inPubMed Google Scholar * Tim Stearns View author publications You can also search for this author

inPubMed Google Scholar * Brunella Franco View author publications You can also search for this author inPubMed Google Scholar * Qing Zhong View author publications You can also search for

this author inPubMed Google Scholar CONTRIBUTIONS Z.T., M.G.L. and T.R.S. performed the experiments; S.C. carried out mass spectrometry analysis; M.Z., T.S. and B.F. provided technical and

intellectual support; Z.T. and Q.Z. conceived the project, designed the experiments, analysed the data and wrote the manuscript with the help of all authors. CORRESPONDING AUTHOR

Correspondence to Qing Zhong. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. EXTENDED DATA FIGURES AND TABLES EXTENDED DATA FIGURE 1

LC3-INTERACTING PROTEIN PCM1 IS NOT REQUIRED FOR AUTOPHAGY. A, PCM1 associates with LC3, GATE16 and GABARAP. Silver staining of LC3, GATE16 or GABARAP complexes purified from U2OS cells that

stably express ZZ–Flag–LC3, ZZ–Flag–GATE16, or ZZ–Flag–GABARAP in normal medium or subjected to 2 h Earle’s balanced salt solution (EBSS) starvation. Both PCM1 and p62 were identified by

mass spectrometry analysis. B, PCM1 is not required for autophagy. Western blotting analysis of p62, LC3-I/II, PCM1 levels in control or _PCM1_ shRNA knockdown U2OS cells in normal medium or

subjected to rapamycin treatment; quantified LC3-II level was normalized with β-tubulin. C, OFD1 messenger RNA levels remain unchanged upon serum starvation. Quantitative analysis of

messenger RNA levels of OFD1 in _Atg5_+/+ and _Atg5__−/−_ MEFs in normal medium or subjected to 24 h serum starvation. _OFD1_ mRNA levels were detected by quantitative RT–PCR and plotted

after normalization. Similar results were obtained in three independent experiments. EXTENDED DATA FIGURE 2 PCM1 IS REQUIRED FOR OFD1 CENTRIOLAR SATELLITE LOCALIZATION. A, Representative

confocal images of OFD1 and PCM1 localization from control or PCM1 knockdown U2OS cells in normal medium. Data shown represent 100 cells per well in triplicate samples. B, Quantified

percentage of cells with PCM1 positive centriolar satellite OFD1 in A. Data shown represent 100 cells per well in triplicate samples. ***_P_ < 0.001, two-tailed unpaired student’s

_t_-test. C, LC3 partially colocalizes with PCM1 upon serum starvation. Representative confocal images of Myc–LC3 and PCM1 colocalization in U2OS cells expressing Myc–LC3 in normal medium or

subjected to 24 h serum starvation. Arrows denote colocalized LC3 (green) and PCM1 (red) puncta. Data shown represent 100 cells per well in triplicate samples. D, Quantified percentage of

cells with colocalization of Myc–LC3 and PCM1 in C. ***_P_ < 0.001, two-tailed unpaired student’s _t_-test. Similar results were observed in three independent experiments. EXTENDED DATA

FIGURE 3 LC3 PARTIALLY COLOCALIZES WITH OFD1 BUT NOT WITH Γ-TUBULIN. A, LC3 colocalizes with OFD1 when the lysosome activity is blocked. Representative confocal images of Myc–LC3 and OFD1

colocalization in U2OS cells that stably express Myc–LC3 in normal medium or subjected to 2 h 50 nM bafilomycin A1 (Baf) or 100 µM CQ. Data shown represent 100 cells per well in triplicate

samples. B, Quantified percentage of cells with colocalization of Myc–LC3 and OFD1 in A. C, LC3 does not colocalize with centrioles. Representative confocal images of LC3 and γ-tubulin

colocalization in U2OS cells in normal medium or subjected to 24 h serum starvation. Data shown represent 100 cells per well in triplicate samples. D, Quantified percentage of cells with

colocalization of LC3 and γ-tubulin in C. Similar results were obtained in three independent experiments. EXTENDED DATA FIGURE 4 OFD1 BUT NOT PCM1 AT CENTRIOLAR SATELLITES WAS DEGRADED BY

AUTOPHAGY. A, OFD1 accumulates at centriolar satellites in CQ-treated cells. Representative confocal images of EGFP–OFD1 and PCM1 colocalization in _Atg5_+/+ cells expressing EGFP–OFD1

subjected to 24 h serum starvation or 20 µM CQ. B, Quantified percentage of cells with centriolar satellite OFD1 in A. Data shown represent mean _±_ s.d. for 100 cells per well in triplicate

samples. ***_P_ < 0.001, two-tailed unpaired student’s _t_-test. C, PCM1 is not degraded upon serum starvation. Representative confocal images of PCM1 centriolar satellite staining in

_Atg5_+/+ cells in normal medium or subjected to 24 h serum starvation. Data shown represent mean _±_ s.d. for 200 cells per well in triplicate samples. D, Quantified percentage of cells

with PCM1 centriolar satellite staining in C. E, OFD1 but not PCM1 is degraded from centriolar satellites upon serum starvation. Representative confocal images of PCM1 and OFD1

colocalization in _Atg5_+/+ cells in normal medium or subjected to 24 h serum starvation. Data shown represent 200 cells per well in triplicated samples. Enlarged images were shown in the

left bottom panels. Similar results were obtained in three independent experiments. EXTENDED DATA FIGURE 5 THE TURNOVER RATE OF CENTRIOLAR SATELLITE OFD1 IS FASTER THAN OFD1 AT CENTRIOLES.

A, Centriolar satellite OFD1 has a shorter half-life compared to OFD1 at centrioles. Quantified percentage of cells with OFD1 at centrioles or at centriolar satellites from _Atg5_+/+ and

_Atg5__−/−_ MEFs in normal medium or subjected to 75 µM cycloheximide (CHX) with indicated time points. Data shown represent 200 cells per well in triplicate samples. B, Centriolar satellite

OFD1 but not centriole OFD1 degrades upon serum starvation. Quantified percentage of cells with OFD1 at centrioles or at centriolar satellites from _Atg5_+/+ and _Atg5__−/−_ MEFs in normal

medium or subjected to serum starvation with indicated time points. Data shown represent 200 cells per well in triplicate samples. Similar results were obtained in three independent

experiments. EXTENDED DATA FIGURE 6 AUTOPHAGY REGULATES PRIMARY CILIOGENESIS IN A CELL CYCLE INDEPENDENT MANNER. A, FACS analysis of _Atg5_+/+ and _Atg5__−/−_ MEFs in normal medium or

subjected to 24 h serum starvation. Data shown represent 106 cells per well in triplicate samples. B, Primary ciliogenesis is less efficient when the lysosome activity is blocked in MEFs.

Representative confocal images of primary cilia formed in _Atg5_+/+ MEFs subjected to 24 h serum starvation alone or combined with 20 µM CQ treatment. C, Quantified percentage of cells with

primary cilia in B. D, Quantified length of primary cilia in B. E, Degradation of OFD1 is also blocked in _Atg3__−/−_ MEFs. Western blot analysis of OFD1, p62, LC3-I/II and BBS4 protein

levels in MEFs with indicated genotypes in normal medium or subjected to 24 h serum starvation; quantified OFD1 levels were normalized with β-tubulin. F, G, Primary ciliogenesis is also

defective in _Atg3__−/−_ MEFs. F, Quantified percentage of cells with primary cilia in _Atg3_+/+ and _Atg3__−/−_ MEFs in normal medium or subjected to 24 h serum starvation. G, Quantified

length of primary cilia formed in _Atg3_+/+ and _Atg3__−/−_ MEFs as described in F. C, D, F, G, Data shown represent mean _±_ s.d. for 100 cells per well in triplicate samples. ***_P_ < 

0.001, two-tailed unpaired student’s _t_-test. Similar results were obtained in three independent experiments. EXTENDED DATA FIGURE 7 BBS4 RECRUITMENT TO PRIMARY CILIA IS DEFECTIVE IN

_ATG5__−/−_ MEFS. A, Representative confocal images of _Atg5_+/+ and _Atg5__−/−_ MEFs expressing Myc–BBS4 subjected to 24 h serum starvation. Scale bar 5 µm. B, Quantified percentage of

cells with Myc–BBS4 translocation into primary cilia in _Atg5_+/+ and _Atg5__−/−_ MEFs. Data shown represent mean _±_ s.d. for 100 cells per well in triplicate samples. ***_P_ < 0.001,

two-tailed unpaired student’s _t_-test. Similar results were obtained in three independent experiments. EXTENDED DATA FIGURE 8 PARTIAL SHRNA KNOCKDOWN OF OFD1 LEADS TO DEPLETION OF OFD1 FROM

CENTRIOLAR SATELLITES IN _ATG5_+/+ AND _ATG5__−/−_ MEFS. A, Western blot analysis of OFD1 in MEFs with indicated genotypes in normal medium. Quantified OFD1 levels were normalized with

β-tubulin. KD, knockdown. B, Quantified percentage of cells with centriolar satellite OFD1 in MEFs with indicated genotypes in normal medium. Data shown represent mean _±_ s.d. percentage of

cells with centriolar satellite OFD1 for 100 cells per well in triplicate samples. ***_P_ < 0.001, two-tailed unpaired student’s _t_-test. C, D, OFD1 was depleted from centriolar

satellites but not centrioles in OFD1 knockdown MEFs. Representative confocal images of OFD1 and axoneme marker acetylated tubulin in C or centriole marker γ-tubulin in D in MEFs with

indicated genotypes in normal medium. Data shown represent 100 cells per well in triplicate samples. Similar results were obtained in three independent experiments. EXTENDED DATA FIGURE 9

KNOCKDOWN OF OFD1 IN WILD-TYPE MEFS PROMOTES PRIMARY CILIOGENESIS. A, Representative confocal images of primary cilia formed in MEFs with indicated genotypes in normal medium (Un) or

subjected to 24 h serum starvation (SS). Quantified percentage of cells with primary cilia and the length of primary cilia from MEFs with indicated genotypes were shown in the bottom panels.

Data shown represent mean _±_ s.d. for 100 cells per well in triplicate samples. B, Representative confocal images of primary cilia formed in MEFs with indicated genotypes subjected to 24 h

serum starvation. The primary cilia formed are positive for both axoneme marker acetylated tubulin and ciliary membrane marker ARL13B. Data shown represent 100 cells per well in triplicate

samples. Similar results were obtained in three independent experiments. EXTENDED DATA FIGURE 10 PARTIAL KNOCKDOWN OFD1 IN MCF7 CELLS DEPLETES OFD1 FROM CENTRIOLAR SATELLITES AND PROMOTES

PRIMARY CILIOGENESIS. A, B, OFD1 was depleted from centriolar satellites in OFD1 shRNA knockdown MCF7 cells. A, Representative confocal images of relative localization of OFD1 with axoneme

marker acetylated tubulin in MCF7 OFD1 knockdown clone (C19). Data shown represent 100 cells per well in triplicate samples. B, Representative confocal images of OFD1 and centriole marker

γ-tubulin from C19. Data shown represent 100 cells per well in triplicate samples. C, Quantified percentage of parental MCF7 and C19 cells with centriolar satellite OFD1. Data shown

represent mean _±_ s.d. for 100 cells per well in triplicate samples. ***_P_ < 0.001, two-tailed unpaired student’s _t_-test. D–F, Primary cilia formed in OFD1 knockdown C19 MCF7 cells

are positive for ciliary markers. Representative confocal images of primary cilia formed in C19 subjected to 72 h serum starvation. Cilia were positive for ciliary membrane marker ARL13B,

axoneme marker acetylated tubulin and intraflagellar transport protein IFT88. Similar results were obtained in three independent experiments. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1

POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Tang, Z., Lin, M.,

Stowe, T. _et al._ Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites. _Nature_ 502, 254–257 (2013). https://doi.org/10.1038/nature12606 Download citation *

Received: 19 October 2012 * Accepted: 29 August 2013 * Published: 02 October 2013 * Issue Date: 10 October 2013 * DOI: https://doi.org/10.1038/nature12606 SHARE THIS ARTICLE Anyone you share

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