CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function
Saumil Sethna1, Patrick A Scott2, Arnaud P J Giese1
1Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
Nature Communications
|June 24, 2021
Summary
Calcium and integrin binding protein 2 (CIB2) deficiency causes age-related macular degeneration (AMD) pathologies in mice by impairing autophagy. Restoring CIB2 function may treat AMD and related disorders.
Area of Science:
- Ophthalmology
- Neurodegenerative Diseases
- Molecular Biology
Background:
- Age-related macular degeneration (AMD) is a complex neurodegenerative disease where impaired autophagy is implicated.
- The precise molecular causes of AMD remain largely unknown.
Purpose of the Study:
- To investigate the role of calcium and integrin binding protein 2 (CIB2) in AMD pathogenesis.
- To explore the link between CIB2, autophagy, and mTORC1 signaling in AMD and other diseases.
Main Methods:
- Utilized CIB2-deficient mice to model AMD-related pathologies.
- Analyzed retinal pigment epithelium (RPE)/choroid tissues from mice and post-mortem human dry AMD samples.
- Investigated molecular mechanisms involving CIB2, mTORC1, and Rheb signaling.
- Examined CIB2's effect on patient-derived fibroblasts from lymphangioleiomyomatosis (LAM) cases.
Main Results:
- CIB2 deficiency in mice led to AMD-like features: RPE deposits, drusen marker accumulation (APOE, C3, Aβ, cholesterol), and vision impairment.
- CIB2 deficiency caused reduced autophagic clearance and lysosomal function, with increased mTORC1 signaling.
- Similar molecular deficits were found in human dry AMD tissues.
- CIB2 negatively regulates mTORC1 by binding to inactive Rheb; CIB2 overexpression reduced mTORC1 in LAM cells.
Conclusions:
- CIB2 is crucial for maintaining retinal health and autophagic homeostasis, and its deficiency contributes to AMD.
- Dysregulation of the CIB2-mTORC1 axis is a key mechanism in AMD and potentially other diseases with mTORC1 hyperactivity.
- Targeting CIB2 or the mTORC1 pathway offers therapeutic potential for AMD and related conditions.
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