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CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function
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CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function
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Journal Article
CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function
2021
Overview
Age-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.
Age-related macular degeneration (AMD) has been connected to deficits in autophagy. Here, the authors demonstrate, in mice and dry-AMD patient samples, that calcium and integrin binding protein 2 (CIB2) regulates Rheb-mTORC1 signaling axis, and subsequently autophagy.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/19
/ 14/28
/ 14/35
/ 14/63
/ 38
/ 38/1
/ 38/70
/ 64/60
/ 692/4017
/ Age
/ Animals
/ Autopsy
/ Calcium
/ Calcium-Binding Proteins - deficiency
/ Calcium-Binding Proteins - genetics
/ Humanities and Social Sciences
/ Humans
/ Macular Degeneration - genetics
/ Macular Degeneration - pathology
/ Mechanistic Target of Rapamycin Complex 1 - genetics
/ Mechanistic Target of Rapamycin Complex 1 - metabolism
/ Mice
/ Proteins
/ Retinal Pigment Epithelium - metabolism
/ Science
