Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

• DOI: 10.1128/jvi.01904-16
• Publication Date: 2017-01-12T02:32:08Z
• Authors: Nicholas L. Cianc...; Stacey Chung; Danny Manor; Cathleen R. Carlin
• Keywords: Lipid raft; Transport protein

Human adenoviruses (Ads) generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how virus counteracts host defense mechanisms. This study had two goals. First, we wished determine molecular basis cholesterol homeostatic responses induced by early region 3 membrane protein RIDα via its direct interaction with sterol-binding ORP1L, a member evolutionarily conserved family oxysterol-binding (OSBP)-related proteins (ORPs). Second, this regulates innate immunity adenovirus. ORP1L is known form highly dynamic contacts endoplasmic reticulum-resident VAP that regulate late endosome function under regulation Rab7-GTP. Our studies have demonstrated ORP1L-VAP complexes also support transport LDL-derived from endosomes reticulum, where it was converted cholesteryl esters stored lipid droplets when bound RIDα. The virally mechanism counteracted defects predominant pathway regulated endosomal Niemann-Pick type C 1 (NPC1) arising during stages viral infection. However, unlike NPC1, did not reconstitute reticulum pools SREBP transcription factors. RIDα-induced trafficking attenuated proinflammatory signaling Toll-like receptor 4, which has central role Ad pathogenesis tightly cholesterol-rich "lipid rafts." Collectively, these data show utilizes way distinct normal uninfected cells fine-tune raft adenovirus endosomes.IMPORTANCE Early encoded human attenuate immune-mediated pathology been particularly rich source information regarding intracellular trafficking. 3-encoded provided fundamental new mechanisms nonvesicular flow at between different organelles. We describe delivers esterified droplets. Although are attracting renewed interest standpoint physiology diseases, including those resulting infections, experimental model systems for evaluating why they accumulate still limited. revealed an intriguing relationship may represent paradigm viruses utilizing