Adenovirus RID-alpha activates an autonomous cholesterol regulatory mechanism that rescues defects linked to Niemann-Pick disease type C.
Host-pathogen interactions are important model systems for understanding fundamental cell biological processes. In this study, we describe a cholesterol-trafficking pathway induced by the adenovirus membrane protein RID-alpha that also subverts the cellular autophagy pathway during early stages of an acute infection. A palmitoylation-defective RID-alpha mutant deregulates cholesterol homeostasis and elicits lysosomal storage abnormalities similar to mutations associated with Niemann-Pick type C (NPC) disease. Wild-type RID-alpha rescues lipid-sorting defects in cells from patients with this disease by a mechanism involving a class III phosphatidylinositol-3-kinase. In contrast to NPC disease gene products that are localized to late endosomes/lysosomes, RID-alpha induces the accumulation of autophagy-like vesicles with a unique molecular composition. Ectopic RID-alpha regulates intracellular cholesterol trafficking at two distinct levels: the egress from endosomes and transport to the endoplasmic reticulum necessary for homeostatic gene regulation. However, RID-alpha also induces a novel cellular phenotype, suggesting that it activates an autonomous cholesterol regulatory mechanism distinct from NPC disease gene products.
Cianciola
Nicholas L
NL
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
Carlin
Cathleen R
CR
D017503:Adenovirus E3 Proteins / Q000378:metabolism / Q000502:physiology*; D000260:Adenoviruses, Human / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism* / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D052556:Niemann-Pick Disease, Type C / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D019308:Palmitic Acid / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000145:classification / Q000502:physiology
D017503:Adenovirus E3 Proteins; C113428:E3-13.7 protein, human adenovirus; D008565:Membrane Proteins; D019308:Palmitic Acid; D002784:Cholesterol; D019869:Phosphatidylinositol 3-Kinases