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bioRxiv · 10.1101/2020.09.18.302265

CIB2 regulates autophagy via Rheb-mTORC1 signaling axis

Sethna, S. S.·Bernstein, S. L.·Jian, X.·Riazuddin, S.·Randazzo, P. A.·Ahmed, Z. M.
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Abstract

Age-related macular degeneration (AMD), a multifactorial neurodegenerative disorder, is the most common cause of vision loss in the elderly. Deficits in autophagy have been associated with age-related retinal pigment epithelium (RPE) pathology in mice, and dry-AMD in humans. In this study, we establish that the calcium and integrin binding protein 2 (CIB2) regulates autophagy in the RPE via Rheb-mTORC1 signaling axis. Cib2 mutant mice have reduced autophagic clearance in RPE and increased mTORC1 signaling - a negative regulator of autophagy. Concordant molecular deficits were also observed in RPE/choroid tissues from humans affected with dry AMD. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to nucleotide empty or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in aging, Tuberous sclerosis complex (TSC), and lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts and Tsc2 null cell line down-regulates hyperactive mTORC1 signaling. Thus, our findings have significant ramifications for the etiology of AMD and mTORC1 hyperactivity disorders and treatments.

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Sethna, S. S., Bernstein, S. L., Jian, X., Riazuddin, S., Randazzo, P. A., Ahmed, Z. M.. 2020-09-19. CIB2 regulates autophagy via Rheb-mTORC1 signaling axis. https://doi.org/10.1101/2020.09.18.302265

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