CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function
Scott, Patrick A
Giese, Arnaud P J
Randazzo, Paul A
Redmond, T Michael
Bernstein, Steven L
Ahmed, Zubair M
MetadataShow full item record
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.
Mechanistic Target of Rapamycin Complex 1
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/16099
- The amino acid transporter SLC36A4 regulates the amino acid pool in retinal pigmented epithelial cells and mediates the mechanistic target of rapamycin, complex 1 signaling.
- Authors: Shang P, Valapala M, Grebe R, Hose S, Ghosh S, Bhutto IA, Handa JT, Lutty GA, Lu L, Wan J, Qian J, Sergeev Y, Puertollano R, Zigler JS Jr, Xu GT, Sinha D
- Issue date: 2017 Apr
- Loss of NRF-2 and PGC-1α genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration.
- Authors: Felszeghy S, Viiri J, Paterno JJ, Hyttinen JMT, Koskela A, Chen M, Leinonen H, Tanila H, Kivinen N, Koistinen A, Toropainen E, Amadio M, Smedowski A, Reinisalo M, Winiarczyk M, Mackiewicz J, Mutikainen M, Ruotsalainen AK, Kettunen M, Jokivarsi K, Sinha D, Kinnunen K, Petrovski G, Blasiak J, Bjørkøy G, Koskelainen A, Skottman H, Urtti A, Salminen A, Kannan R, Ferrington DA, Xu H, Levonen AL, Tavi P, Kauppinen A, Kaarniranta K
- Issue date: 2019 Jan
- MicroRNA-29 enhances autophagy and cleanses exogenous mutant αB-crystallin in retinal pigment epithelial cells.
- Authors: Cai J, Zhang H, Zhang YF, Zhou Z, Wu S
- Issue date: 2019 Jan 1
- Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies.
- Authors: Cheng SY, Cipi J, Ma S, Hafler BP, Kanadia RN, Brush RS, Agbaga MP, Punzo C
- Issue date: 2020 Jun 9
- Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/βA3/A1-crystallin via V-ATPase-MTORC1 signaling.
- Authors: Valapala M, Wilson C, Hose S, Bhutto IA, Grebe R, Dong A, Greenbaum S, Gu L, Sengupta S, Cano M, Hackett S, Xu G, Lutty GA, Dong L, Sergeev Y, Handa JT, Campochiaro P, Wawrousek E, Zigler JS Jr, Sinha D
- Issue date: 2014 Mar