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dc.contributor.authorSethna, Saumil
dc.contributor.authorScott, Patrick A
dc.contributor.authorGiese, Arnaud P J
dc.contributor.authorDuncan, Todd
dc.contributor.authorJian, Xiaoying
dc.contributor.authorRiazuddin, Sheikh
dc.contributor.authorRandazzo, Paul A
dc.contributor.authorRedmond, T Michael
dc.contributor.authorBernstein, Steven L
dc.contributor.authorRiazuddin, Saima
dc.contributor.authorAhmed, Zubair M
dc.date.accessioned2021-06-28T15:14:35Z
dc.date.available2021-06-28T15:14:35Z
dc.date.issued2021-06-23
dc.identifier.urihttp://hdl.handle.net/10713/16099
dc.description.abstractAge-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling-a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to 'nucleotide empty' or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.en_US
dc.description.urihttps://doi.org/10.1038/s41467-021-24056-1en_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofNature Communicationsen_US
dc.subjectCIB2en_US
dc.subjectmTORC1en_US
dc.subject.meshAutophagy-Related Proteinsen_US
dc.subject.meshMacular Degenerationen_US
dc.subject.meshMechanistic Target of Rapamycin Complex 1en_US
dc.titleCIB2 regulates mTORC1 signaling and is essential for autophagy and visual functionen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41467-021-24056-1
dc.identifier.pmid34162842
dc.source.volume12
dc.source.issue1
dc.source.beginpage3906
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland


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