Functional interaction between autophagy and ciliogenesis

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Summary

Nutrient deprivation is a stimulus shared by both autophagy and the formation of primary cilia. The recently discovered role of primary cilia in nutrient sensing and signaling motivated us to explore the possible functional interactions between this signaling hub and autophagy. Here we show that part of the molecular machinery involved in ciliogenesis also participates in the early steps of the autophagic process. Signaling from the cilia, such as that from the Hedgehog pathway, induces autophagy by acting directly on essential autophagy-related proteins strategically located in the base of the cilium by ciliary trafficking proteins. While abrogation of ciliogenesis partially inhibits autophagy, blockage of autophagy enhances primary cilia growth and cilia-associated signaling during normal nutritional conditions. We propose that basal autophagy regulates ciliary growth through the degradation of proteins required for intraflagellar transport. Compromised ability to activate the autophagic response may underlie the basis of some common ciliopathies.

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Most cited references 19

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Guidelines for the use and interpretation of assays for monitoring autophagy.

C N Estevez, S Lee, Qing Zhong … (2012)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

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Patched1 regulates hedgehog signaling at the primary cilium.

Rajat Rohatgi, Ljiljana Milenkovic, Phillip Scott (2007)

Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia. When Shh bound to Ptc1, Ptc1 left the cilia, leading to accumulation of Smo and activation of signaling. Thus, primary cilia sense Shh and transduce signals that play critical roles in development, carcinogenesis, and stem cell function.

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The primary cilium at a glance.

Peter Satir, Dan B Pedersen, Bo Christensen (2010)

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 2 January 2014

Publication date (Electronic): 02 October 2013

Publication date (Print): 10 October 2013

Publication date PMC-release: 10 April 2014

Volume: 502

Issue: 7470

Pages: 194-200

Affiliations

[1 ]Department of Development and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA

[2 ]Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA

[3 ]Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA

[4 ]INSERM U845; Paris-Descartes University, Paris, France

[5 ]INSERM U984; University Paris-Sud 11; Châtenay-Malabry, France

Author notes

[* ]Corresponding authors: A.M. Cuervo; Phone: 718 340 2689; Fax: 718 430 8975; ana-maria.cuervo@ 123456einstein.yu.edu ; P. Satir; Phone: 718 340 4061; Fax: 718 430 8934; peter.satir@ 123456einstein.yu.edu

Article

Manuscript ID: NIHMS523507

DOI: 10.1038/nature12639

PMC ID: 3896125

PubMed ID: 24089209

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Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

Funding

Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK

Award ID: R01 DK098408 || DK

Funded by: National Institute on Aging : NIA

Award ID: P30 AG038072 || AG

Funded by: National Institute on Aging : NIA

Award ID: P01 AG031782 || AG

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Functional interaction between autophagy and ciliogenesis

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Most cited references 19

Guidelines for the use and interpretation of assays for monitoring autophagy.

Patched1 regulates hedgehog signaling at the primary cilium.

The primary cilium at a glance.

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Cited by 115

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