CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function

Saumil Sethna, Patrick A. Scott, Arnaud P. J. Giese, Todd Duncan, Xiaoying Jian, Sheikh Riazuddin, Paul A. Randazzo, T. Michael Redmond, Steven L. Bernstein, Saima Riazuddin and Zubair M. Ahmed ()
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Saumil Sethna: University of Maryland School of Medicine
Patrick A. Scott: University of Louisville
Arnaud P. J. Giese: University of Maryland School of Medicine
Todd Duncan: Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health
Xiaoying Jian: Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health
Sheikh Riazuddin: Allama Iqbal Medical College, University of Health Sciences
Paul A. Randazzo: Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health
T. Michael Redmond: Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health
Steven L. Bernstein: University of Maryland School of Medicine
Saima Riazuddin: University of Maryland School of Medicine
Zubair M. Ahmed: University of Maryland School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24056-1

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