2021
DOI: 10.15252/embr.202052173
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OCRL regulates lysosome positioning and mTORC1 activity through SSX2IP‐mediated microtubule anchoring

Abstract: Lysosomal positioning and mTOR (mammalian target of rapamycin) signaling coordinate cellular responses to nutrient levels. Inadequate nutrient sensing can result in growth delays, a hallmark of Lowe syndrome. OCRL mutations cause Lowe syndrome, but the role of OCRL in nutrient sensing is unknown. Here, we show that OCRL is localized to the centrosome by its ASH domain and that it recruits microtubule-anchoring factor SSX2IP to the centrosome, which is important in the formation of the microtubule-organizing ce… Show more

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Cited by 17 publications
(15 citation statements)
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“…We next applied the RAP uptake assay to an ocrl mutant zebrafish line to examine whether neuroepithelial RAP endocytosis and trafficking is impaired in the absence of Ocrl. Ocrl is a inositol-5-phosphatase that acts on pools of PI(4,5)P 2 coupled to membrane remodelling events at multiple stages of the endocytic pathway, which includes clathrin-mediated endocytosis (Choudhury et al, 2009; Erdmann et al, 2007; Nandez et al, 2014), receptor recycling from endosomes (Choudhury et al, 2005; van Rahden et al, 2012; Vicinanza et al, 2011) and lysosome fusion (De Leo et al, 2016; Wang et al, 2021; Zhang et al, 1998). Mutations in OCRL are responsible for Lowe syndrome and Dent 2 disease, X-linked multi-systemic disorders that predominantly affect the eyes, kidney and central nervous system (Bokenkamp and Ludwig, 2016).…”
Section: Resultsmentioning
confidence: 99%
“…We next applied the RAP uptake assay to an ocrl mutant zebrafish line to examine whether neuroepithelial RAP endocytosis and trafficking is impaired in the absence of Ocrl. Ocrl is a inositol-5-phosphatase that acts on pools of PI(4,5)P 2 coupled to membrane remodelling events at multiple stages of the endocytic pathway, which includes clathrin-mediated endocytosis (Choudhury et al, 2009; Erdmann et al, 2007; Nandez et al, 2014), receptor recycling from endosomes (Choudhury et al, 2005; van Rahden et al, 2012; Vicinanza et al, 2011) and lysosome fusion (De Leo et al, 2016; Wang et al, 2021; Zhang et al, 1998). Mutations in OCRL are responsible for Lowe syndrome and Dent 2 disease, X-linked multi-systemic disorders that predominantly affect the eyes, kidney and central nervous system (Bokenkamp and Ludwig, 2016).…”
Section: Resultsmentioning
confidence: 99%
“…Moreover, the reduction in insulin signaling evidenced in our experiments at the cellular level, specifically in conditions of reduction of OCRL1 function, not only would reduce megalin recycling but also would potentially decrease megalin endocytosis as pAKT is required for the efficient megalin-mediated endocytosis of albumin, a physiologically relevant ligand of the receptor present in the proximal tubule ( Silva-Aguiar et al, 2022 ). Regarding AKT activity, it has been recently found that the mTORC1 complex is inactivated in OCRL1 deficient cells ( Madhivanan et al, 2020 ), a defect that triggers a lack of nutrient-sensing ( Wang et al, 2021 ) due to mTORC1 is required for proper insulin signaling ( Saltiel and Kahn, 2001 ). Insulin signaling is also highly dependent on the cell type, something we observed in our experiments, and is associated with insulin receptor trafficking ( Iraburu et al, 2021 ).…”
Section: Discussionmentioning
confidence: 99%
“…It is interesting to note that loss of Lrp2 does not affect neural development in zebrafish, whereas in mammals it causes forebrain malformation, due to defects in SHH endocytosis and morphogen gradient formation (Christ et al, 2012;Kur et al, 2011). This difference may reflect different requirements for SHH signalling between mammals and teleosts, or perhaps differential requirements for LRP family receptors in endocytosis and developmental signalling between the two classes of vertebrates (Willnow and Christ, 2017). Uncovering the complement of receptors that mediate zebrafish neuroepithelial RAP endocytosis may therefore provide further insights into whether and how LRP family members contribute to neural development in zebrafish and possibly in mammals too (Christ et al, 2012;Kur et al, 2011).…”
Section: Journal Of Cell Science • Accepted Manuscriptmentioning
confidence: 99%
“…For genotyping of ocrl mutant adult zebrafish a PCR fragment spanning the SpeI restriction site in the ocrl gene was amplified from genomic DNA prepared from adult fish as previously described (Wilkinson et al, 2013). The resulting 720 bp fragment was digested using SpeI restriction enzyme (New England Biolabs) and the digested product resolved by gel electrophoresis.…”
Section: Genotyping Of Ocrl Mutant Adult Zebrafishmentioning
confidence: 99%
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