The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics

Abstract

During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The contributions of specific lipids, such as cholesterol, to the membranes that form the autophagosome, remain to be fully characterized. Here, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and a corresponding increase in autophagy initiation events. We further show that the ER-localized cholesterol transport protein GRAMD1C functions as a negative regulator of starvation-induced autophagy and that both its cholesterol transport VASt domain and membrane binding GRAM domain are required for GRAMD1C-mediated suppression of autophagy initiation. Similar to its yeast orthologue, GRAMD1C associates with mitochondria through its GRAM domain. Cells lacking GRAMD1C or its VASt domain show increased mitochondrial cholesterol levels and mitochondrial oxidative phosphorylation, suggesting that GRAMD1C may facilitate cholesterol transfer at ER-mitochondria contact sites. Finally, we demonstrate that expression of GRAMD family proteins is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.

The eQTL colocalization and transcriptome-wide association study identify potentially causal genes responsible for economic traits in Simmental beef cattle

“…The eQTLs of GRAMD1C in adipose were related to rear thigh circumference. GRAMD1C is a cholesterol transfer gene that contributes to cholesterol transfer activity [ 76 ]. Both TMTC2 and ZNF613 were GWAS fine-mapped candidate genes for body conformation traits in a previous study [ 50 ].…”

Profiling the LAM family of contact site tethers provides insights into their regulation and function

“…Here, we found that the loss of Lam5 led to increased respiration when the cells were grown in glucose (Figure 2F), as opposed to Lam6, which appears to be required for maintaining normal respiration levels independent of the carbon source (Figure 2E, 2F). Evidence suggests these results are conserved, since loss of one of the human Lam5/6 orthologs, GRAMD1C, also leads to increased oxidative phosphorylation (Ng et al, 2022).…”

Transcriptomic data in tumor‐adjacent normal tissues harbor prognostic information on multiple cancer types

“…GRAMD1A is related to immune infiltration in tumor microenvironments, and expression of GRAMD1A is significantly related to the survival of kidney cancer patients 50 . In fact, GRAMD family expression was associated with the survival outcome of the KIRC cohort 51 . Next, the expression of CYP3A in normal kidney tissue might be involved in tumor development 52 .…”

“… 50 In fact, GRAMD family expression was associated with the survival outcome of the KIRC cohort. 51 Next, the expression of CYP3A in normal kidney tissue might be involved in tumor development. 52 KRT8 overexpression in renal cancer was associated with cell migration and invasion, and was significantly related to poor survival of patients.…”