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FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation

Dunlop, Elaine, Seifan, Sara, Claessens, Tijs, Behrends, Christian, Kamps, Miriam A.F., Rozycka, Ewelina, Kemp, Alain J., Nookala, Ravi K., Blenis, John, Coull, Barry J., Murray, James T., van Steensel, Maurice A.M., Wilkinson, Simon and Tee, Andrew 2014. FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy 10 (10) , pp. 1749-1760. 10.4161/auto.29640

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Abstract

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant condition caused by mutations in the FLCN gene and characterized by benign hair follicle tumors, pneumothorax, and renal cancer. Folliculin (FLCN), the protein product of the FLCN gene, is a poorly characterized tumor suppressor protein, currently linked to multiple cellular pathways. Autophagy maintains cellular homeostasis by removing damaged organelles and macromolecules. Although the autophagy kinase ULK1 drives autophagy, the underlying mechanisms are still being unraveled and few ULK1 substrates have been identified to date. Here, we identify that loss of FLCN moderately impairs basal autophagic flux, while re-expression of FLCN rescues autophagy. We reveal that the FLCN complex is regulated by ULK1 and elucidate 3 novel phosphorylation sites (Ser406, Ser537, and Ser542) within FLCN, which are induced by ULK1 overexpression. In addition, our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). The FLCN-GABARAP association is modulated by the presence of either folliculin-interacting protein (FNIP)-1 or FNIP2 and further regulated by ULK1. As observed by elevation of GABARAP, sequestome 1 (SQSTM1) and microtubule-associated protein 1 light chain 3 (MAP1LC3B) in chromophobe and clear cell tumors from a BHD patient, we found that autophagy is impaired in BHD-associated renal tumors. Consequently, this work reveals a novel facet of autophagy regulation by ULK1 and substantially contributes to our understanding of FLCN function by linking it directly to autophagy through GABARAP and ULK1.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Additional Information: PDF uploaded in accordance with publisher's policies at http://www.sherpa.ac.uk/romeo/issn/1554-8627/ (accessed 1.4.16)
Publisher: Taylor & Francis
ISSN: 1554-8627
Date of First Compliant Deposit: 1 April 2016
Date of Acceptance: 18 June 2014
Last Modified: 28 Jun 2019 07:54
URI: http://orca-mwe.cf.ac.uk/id/eprint/79277

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