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Autophagy. 2014 Oct 1;10(10):1749-60. doi: 10.4161/auto.29640. Epub 2014 Jul 22.

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

Author information

1
Institute of Cancer and Genetics, Cardiff University; Heath Park, Cardiff, Wales UK.
2
Institute of Cancer and Genetics, Cardiff University; Heath Park, Cardiff, Wales UK; Department of Dermatology; GROW School for Oncology and Developmental Biology; Maastricht University Medical Center; Maastricht, Netherlands.
3
Frankfurt Institute for Molecular Life Sciences (FMLS) and Institute of Biochemistry II; Goethe University School of Medicine; Frankfurt, Germany.
4
Department of Dermatology; GROW School for Oncology and Developmental Biology; Maastricht University Medical Center; Maastricht, Netherlands.
5
Centre for Cancer Research and Cell Biology; School of Medicine, Dentistry and Biomedical Science; Queen's University Belfast; Belfast, UK.
6
Institute of Genetics and Molecular Medicine; Edinburgh Cancer Research UK Centre; University of Edinburgh; Edinburgh, UK.
7
Department of Biochemistry; University of Cambridge; Cambridge, UK.
8
Department of Cell Biology; Harvard Medical School; Boston, MA USA.
9
Centre for Cancer Research and Cell Biology; School of Medicine, Dentistry and Biomedical Science; Queen's University Belfast; Belfast, UK; Trinity Biomedical Sciences Institute; School of Biochemistry and Immunology; Trinity College; Dublin, Ireland.
10
Department of Dermatology; GROW School for Oncology and Developmental Biology; Maastricht University Medical Center; Maastricht, Netherlands; Immunos; Institute of Medical Biology; Singapore.

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.

KEYWORDS:

BHD; FLCN; GABARAP; MAP1LC3B; SQSTM1; ULK1; autophagy

PMID:
25126726
PMCID:
PMC4198360
DOI:
10.4161/auto.29640
[Indexed for MEDLINE]
Free PMC Article

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