Restructured membrane contacts rewire organelles for human cytomegalovirus infection. Author Katelyn Cook, Elene Tsopurashvili, Jason Needham, Sunnie Thompson, Ileana Cristea Publication Year 2022 Type Journal Article Abstract Membrane contact sites (MCSs) link organelles to coordinate cellular functions across space and time. Although viruses remodel organelles for their replication cycles, MCSs remain largely unexplored during infections. Here, we design a targeted proteomics platform for measuring MCS proteins at all organelles simultaneously and define functional virus-driven MCS alterations by the ancient beta-herpesvirus human cytomegalovirus (HCMV). Integration with super-resolution microscopy and comparisons to herpes simplex virus (HSV-1), Influenza A, and beta-coronavirus HCoV-OC43 infections reveals time-sensitive contact regulation that allows switching anti- to pro-viral organelle functions. We uncover a stabilized mitochondria-ER encapsulation structure (MENC). As HCMV infection progresses, MENCs become the predominant mitochondria-ER contact phenotype and sequentially recruit the tethering partners VAP-B and PTPIP51, supporting virus production. However, premature ER-mitochondria tethering activates STING and interferon response, priming cells against infection. At peroxisomes, ACBD5-mediated ER contacts balance peroxisome proliferation versus membrane expansion, with ACBD5 impacting the titers of each virus tested. Keywords Humans, Cytomegalovirus, Cytomegalovirus Infections, Organelles, Viruses, Herpes Simplex, Peroxisomes, Herpesviridae Infections Journal Nat Commun Volume 13 Issue 1 Pages 4720 Date Published 2022 Aug 11 ISSN Number 2041-1723 DOI 10.1038/s41467-022-32488-6 Alternate Journal Nat Commun PMCID PMC9366835 PMID 35953480 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML