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

Dunlop, Elaine A.; Seifan, Sara; Claessens, Tijs; Behrends, Christian; Kamps, M.; Rozycka, Ewelina; Kemp, Alain J.; Nookala, Ravi K.; Blenis, John; Coull, Barry J.; Murray, James T.; Steensel, M.A.M. van; Wilkinson, Simon; Tee, Andrew R.

doi:10.4161/auto.29640

Cited by 64 publications

(59 citation statements)

References 66 publications

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“…Three of these proteins—GPSM1/AGS3, 31,32 NCOA4 33 and MAPK8IP1/JIP1 34 —had been shown to interact directly (i.e., through in vitro studies) with some members of the Atg8-family. The 15 remaining proteins—PICALM, 35 PCM1, 36 STAT1, 37,38 UBQLN1 and UBQLN2, 39,40 PEG3, 41,42 HTT, 43 SYNPO2, 44 UBR4, 45,46 MAP1S, 47 BCL10, 48 OFD1, 36 FNIP2, 49 APC 50 and CSPG4 50 —have been identified to function in complexes containing Atg8-family proteins in cellulo by co-immunoprecipitation and/or colocalization experiments (Table S2). In line with the functions of the LIRCPs containing experimentally verified LIR motifs (Table S1), it appears that the proteins interacting with Atg8-family members we sorted can be related to the autophagy process in various ways.…”

Section: Resultsmentioning

confidence: 99%

iLIR database: A web resource for LIR motif-containing proteins in eukaryotes

et al. 2016

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Atg8-family proteins are the best-studied proteins of the core autophagic machinery. They are essential for the elongation and closure of the phagophore into a proper autophagosome. Moreover, Atg8-family proteins are associated with the phagophore from the initiation of the autophagic process to, or just prior to, the fusion between autophagosomes with lysosomes. In addition to their implication in autophagosome biogenesis, they are crucial for selective autophagy through their ability to interact with selective autophagy receptor proteins necessary for the specific targeting of substrates for autophagic degradation. In the past few years it has been revealed that Atg8-interacting proteins include not only receptors but also components of the core autophagic machinery, proteins associated with vesicles and their transport, and specific proteins that are selectively degraded by autophagy. Atg8-interacting proteins contain a short linear LC3-interacting region/LC3 recognition sequence/Atg8-interacting motif (LIR/LRS/AIM) motif which is responsible for their interaction with Atg8-family proteins. These proteins are referred to as LIR-containing proteins (LIRCPs). So far, many experimental efforts have been carried out to identify new LIRCPs, leading to the characterization of some of them in the past 10 years. Given the need for the identification of LIRCPs in various organisms, we developed the iLIR database (https://ilir.warwick.ac.uk) as a freely available web resource, listing all the putative canonical LIRCPs identified in silico in the proteomes of 8 model organisms using the iLIR server, combined with a Gene Ontology (GO) term analysis. Additionally, a curated text-mining analysis of the literature permitted us to identify novel putative LICRPs in mammals that have not previously been associated with autophagy.

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Section: Resultsmentioning

confidence: 99%

iLIR database: A web resource for LIR motif-containing proteins in eukaryotes

et al. 2016

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“…Loss of FLCN in these models resulted in constitutive activation of AMPK, which induced autophagy, inhibited apoptosis, and improved cellular energetics (36,37). These models are however at odds with the suggestion that autophagy was reduced in BHD-associated tumor tissue (38). The role of the FLCN/FNIP complex in negatively regulating AMPK was also apparent in Fnip1 mutant B cells, which showed increased phosphorylation of ULK1, a direct target of AMPK, and staining of LC3, a proxy for autophagy.…”

Section: Discussionmentioning

confidence: 97%

Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity

Siggs

Stockenhuber

Deobagkar-Lele

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Folliculin (FLCN) is a tumor-suppressor protein mutated in the BirtHogg-Dubé (BHD) syndrome, which associates with two paralogous proteins, folliculin-interacting protein (FNIP)1 and FNIP2, forming a complex that interacts with the AMP-activated protein kinase (AMPK). Although it is clear that this complex influences AMPK and other metabolic regulators, reports of its effects have been inconsistent. To address this issue, we created a recessive lossof-function variant of Fnip1. Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells. FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation, with close parallels to mice and humans bearing gain-of-function mutations in the γ2 subunit of AMPK. Concordantly, γ2-specific AMPK activity was elevated in neonatal FNIP1-deficient myocardium, whereas AMPK-dependent unc-51-like autophagy activating kinase 1 (ULK1) phosphorylation and autophagy were increased in FNIP1-deficient B-cell progenitors. These data support a role for FNIP1 as a negative regulator of AMPK.irt-Hogg-Dubé (BHD) syndrome is a hereditary condition caused by germ-line or somatic mutations of the folliculin (FLCN) tumor-suppressor gene (1) and characterized by cutaneous hamartomas, pulmonary cysts, and an increased risk of renal cancer (2).FLCN forms a complex with paralogous folliculin interacting proteins, folliculin-interacting protein (FNIP)1 and FNIP2, both of which bind the C terminus of FLCN with the potential to form homo-or heterotrimeric multimers (3-5). FLCN is a nonredundant component of the FLCN/FNIP1/FNIP2 complex, whereas FNIP1 and FNIP2 appear to be functionally redundant in several tissues. This distinction is illustrated by the fact that kidney-specific deletion of mouse Flcn or compound deletion of Fnip1 and Fnip2 is sufficient to cause renal tumors, and yet deletions of Fnip1 or Fnip2 alone are not (6). This redundancy is consistent with the equivalent expression of Fnip1 and Fnip2 mRNA in kidney tissue (6). In contrast, FNIP1 is nonredundant in other tissues, including bone marrow, myocardium, and skeletal muscle: all of which express relatively more Fnip1 than Fnip2 (6-9).FNIP1 and FNIP2 also bind to the α, β, and γ subunits of the heterotrimeric AMP-activated protein kinase (AMPK) complex (3, 4). A critical regulator of cellular metabolism, AMPK senses and is activated by increased concentrations of AMP and ADP in the energy-depleted cell and subsequently phosphorylates an array of regulatory targets to restore cellular energy status (10). The multifaceted roles of AMPK include growth suppression by inhibiting synthesis of cellular macromolecules, in particular, through phosphorylation of the TSC2 tumor suppressor and inhibition of the mammalian target of rapamycin complex (mTORC)1 signaling pathway (11). AMPK also promotes autophagy via multiple pathways including mTORC1...

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“…FLCN forms a complex with FNIP1 and FNIP2 [11–13] to regulate multiple cellular processes, including energy sensing [14–16], differentiation [17], autophagy [18, 19], and apoptosis [20–23]. However, how this complex senses nutrient availability to control renal cancer tumorigenesis has remained elusive.…”

Section: Discussionmentioning

confidence: 99%

Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression

et al. 2016

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Folliculin-interacting protein 1 and 2 (FNIP1 and FNIP2) play critical roles in preventing renal malignancy through their association with the tumor suppressor FLCN. Mutations in FLCN are associated with Birt-Hogg-Dubé (BHD) syndrome, a rare disorder with increased risk of renal cancer. Recent studies indicated that FNIP1/FNIP2 double knockout mice display enlarged polycystic kidneys and renal carcinoma, which phenocopies FLCN knockout mice, suggesting that these two proteins function together to suppress renal cancer. However, the molecular mechanism functionally linking FNIP1/FNIP2 and FLCN remains largely elusive. Here, we demonstrated that FNIP2 protein is unstable and subjected to proteasome-dependent degradation via β-TRCP and Casein Kinase 1 (CK1)-directed ubiquitination in a nutrition-dependent manner. Degradation of FNIP2 leads to lysosomal dissociation of FLCN and subsequent lysosomal association of mTOR, which in turn promotes the proliferation of renal cancer cells. These results indicate that SCFβ-TRCP negatively regulates the FLCN complex by promoting FNIP degradation and provide molecular insight into the pathogenesis of BHD-associated renal cancer.

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

Cited by 64 publications

References 66 publications

iLIR database: A web resource for LIR motif-containing proteins in eukaryotes

iLIR database: A web resource for LIR motif-containing proteins in eukaryotes

Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity

Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression

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