Rag GTPases mediate amino acid–dependent recruitment of TFEB and MITF to lysosomes

Martina, José A.; Puertollano, Rosa

doi:10.1083/jcb.201209135

Cited by 308 publications

(358 citation statements)

References 31 publications

Supporting

Mentioning

337

Contrasting

Order By: Relevance

“…This phenomenon has been observed in multiple cell types. [23][24][25]33 Consistent with these results, treatment with Torin1 of both HeLa cells and mouse embryonic fibroblasts (MEFs) shifted TFEB to a fast migrating, hypophosphorylated, form that was predominantly localized in the nucleus (Fig. S1A to D).…”

Section: Torin1 Induces Tfeb Dephosphorylation and Nuclear Localizationsupporting

confidence: 74%

“…24,25 MTORC1 is thought to phosphorylate S211 (although no evidence of direct phosphorylation of S211 by MTOR in vitro has been reported to date) creating a docking site for YWHA proteins and leading to cytoplasmic sequestration. Conversely, MTORC1 inhibition by Torin1 induces S211 dephosphorylation (indirectly measured using an antibody against a consensus YWHA binding site 24,33 and more recently using a phospho-S211 antibody 34 ). We observed similar results with a novel phospho-S211 antibody we developed in collaboration with Bethyl that specifically recognizes phosphorylated S211 (Fig.…”

Section: Torin1 Induces Tfeb Dephosphorylation and Nuclear Localizationmentioning

confidence: 99%

See 1 more Smart Citation

Multistep regulation of TFEB by MTORC1

et al. 2017

View full text Add to dashboard Cite

The master regulator of lysosome biogenesis, TFEB, is regulated by MTORC1 through phosphorylation at S211, and a S211A mutation increases nuclear localization. However, TFEB S211A localizes diffusely in both cytoplasm and nucleus and, as we show, retains regulation by MTORC1. Here, we report that endogenous TFEB is phosphorylated at S122 in an MTORC1-dependent manner, that S122 is phosphorylated in vitro by recombinant MTOR, and that S122 is important for TFEB regulation by MTORC1. Specifically, nuclear localization following MTORC1 inhibition is blocked by a S122D mutation (despite S211 dephosphorylation). Furthermore, such a mutation inhibits lysosomal biogenesis induced by Torin1. These data reveal a novel mechanism of TFEB regulation by MTORC1 essential for lysosomal biogenesis.

show abstract

Section: Torin1 Induces Tfeb Dephosphorylation and Nuclear Localizationsupporting

confidence: 74%

Section: Torin1 Induces Tfeb Dephosphorylation and Nuclear Localizationmentioning

confidence: 99%

Multistep regulation of TFEB by MTORC1

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Nutrient deprivation inactivates Rag GTPases, which may mediate the recruitment of mTORC1 and TFEB to lysosomes (35). Nutrient deprivation also results in a rapid decrease in lysosomal PI(3,5)P 2 levels, which have been reported to affect mTOR localization and activity (24,36,37).…”

Section: Resultsmentioning

confidence: 99%

Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation

Wang

Gao

Yang

et al. 2015

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

203

182

View full text Add to dashboard Cite

Upon nutrient starvation, autophagy digests unwanted cellular components to generate catabolites that are required for housekeeping biosynthesis processes. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Here, we report that mucolipin-1 (also known as TRPML1 or ML1), a Ca 2+ channel in the lysosome that regulates many aspects of lysosomal trafficking, plays a central role in this quality-control process. By using Ca 2+ imaging and whole-lysosome patch clamping, lysosomal Ca 2+ release and ML1 currents were detected within hours of nutrient starvation and were potently up-regulated. In contrast, lysosomal Na + -selective currents were not upregulated. Inhibition of mammalian target of rapamycin (mTOR) or activation of transcription factor EB (TFEB) mimicked a starvation effect in fed cells. The starvation effect also included an increase in lysosomal proteostasis and enhanced clearance of lysosomal storage, including cholesterol accumulation in Niemann-Pick disease type C (NPC) cells. However, this effect was not observed when ML1 was pharmacologically inhibited or genetically deleted. Furthermore, overexpression of ML1 mimicked the starvation effect. Hence, lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca 2+ signaling.

show abstract

“…TFEB and TFE3 are recruited to the outer lysosomal membrane by interacting, through their 30-most N-terminal residues, to Rag guanosine triphosphatases (GTPases) [43]. In nutrient-rich conditions, active mTORC1 is recruited to the surface of lysosomes [44], where it phosphorylates Ser142 in TFEB (and also possibly Ser211 in TFEB and Ser321 in TFE3), triggering the binding of these transcription factors to 14-3-3 cytosolic chaperones [45].…”

Section: Mit Transcription Factors Drive Lysosome and Autophagosome Bmentioning

confidence: 99%

“…MITF-A has been shown to localize at the lysosomal membrane, bind to Rag GTPases, and translocate to the nucleus upon mTOR inhibition, mimicking the nutrient-driven regulation of TFEB and TFE3 [43]. In the case of TFEB, Ser142 and Ser211 were known to be required for cytoplasmic retention, as they are the sites for mTORC phosphorylations which promote association with 14-3-3 proteins [45,46].…”

Section: Mitf Expression Correlates With Many Endolysosomal Genesmentioning

confidence: 99%

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

Ploper

Robertis

2015

Pharmacological Research

View full text Add to dashboard Cite

a b s t r a c tCanonical Wnt signaling influences cellular fate and proliferation through inhibition of Glycogen Synthase Kinase (GSK3) and the subsequent stabilization of its many substrates, most notably ␤-Catenin, a transcriptional co-activator. MITF, a melanoma oncogene member of the microphthalmia family of transcription factors (MiT), was recently found to contain novel GSK3 phosphorylation sites and to be stabilized by Wnt. Other MiT members, TFEB and TFE3, are known to play important roles in cellular clearance pathways by transcriptionally regulating the biogenesis of lysosomes and autophagosomes via activation of CLEAR elements in gene promoters of target genes. Recent studies suggest that MITF can also upregulate many lysosomal genes. MiT family members are dysregulated in cancer and are considered oncogenes, but the underlying oncogenic mechanisms remain unclear. Here we review the role of MiT members, including MITF, in lysosomal biogenesis, and how cancers overexpressing MITF, TFEB or TFE3 could rewire the lysosomal pathway, inhibit cellular senescence, and activate Wnt signaling by increasing sequestration of negative regulators of Wnt signaling in multivesicular bodies (MVBs). Microarray studies suggest that MITF expression inhibits macroautophagy. In melanoma the MITF-driven increase in MVBs generates a positive feedback loop between MITF, Wnt, and MVBs.

show abstract

Rag GTPases mediate amino acid–dependent recruitment of TFEB and MITF to lysosomes

Abstract: Active Rag GTPases are required for recruitment of TFEB to lysosomes and its phosphorylation by mTORC1, inhibiting its function under nutrient-rich conditions.

Cited by 308 publications

References 31 publications

Multistep regulation of TFEB by MTORC1

Multistep regulation of TFEB by MTORC1

Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

Contact Info

Product

Resources

About