Infection-Induced Peroxisome Biogenesis Is a Metabolic Strategy for Herpesvirus Replication

Abstract

Summary Viral proteins have evolved to target cellular organelles and usurp their functions for virus replication. Despite the knowledge of these critical functions for several organelles, little is known about peroxisomes during infection. Peroxisomes are primarily metabolic organelles with important functions in lipid metabolism. Here, we discovered that the enveloped viruses human cytomegalovirus (HCMV) and herpes simplex virus (HSV-1) induce the biogenesis of and unique morphological changes to peroxisomes to support their replication. Targeted proteomic quantification revealed a global virus-induced upregulation of peroxisomal proteins. Mathematical modeling and microscopy structural analysis show that infection triggers peroxisome growth and fission, leading to increased peroxisome numbers and irregular disc-like structures. HCMV-induced peroxisome biogenesis increased the phospholipid plasmalogen, thereby enhancing virus production. Peroxisome regulation and dependence were not observed for the non-enveloped adenovirus. Our findings uncover a role of peroxisomes in viral pathogenesis, with likely implications for multiple enveloped viruses.

Spatiotemporal analysis of host cell modification during herpes simplex virus 1 replication

“…We found that our observations matched most descriptions of host cell rearrangements like redistribution and bundling of microtubules [27,28] (13-16 hpi, MOI 3-5), loss of centrosome/MTOC [28] (13 hpi, MOI 5), migration of mitochondria towards perinuclear region [29] ( 6 hpi, MOI 5), and fragmentation of the Golgi apparatus [11,27] (8-12 hpi, MOI 3-10) very well. An exception were peroxisomes, where we did not observe previously described morphological changes, possibly because they were previously identified at later times post infection (16 hpi, MOI 5; Jean Beltran et al [30]).…”

Peroxisomal Membrane Contact Sites in Mammalian Cells

“…For example, the number of peroxisomes increases when rodents are administered fibrate derivatives but decreases rapidly upon withdrawal of the drugs ( Fahimi et al, 1982 ; Yokota, 1986 ; Yokota, 1993 ). Enveloped virus infection induces significant peroxisome biogenesis, promoting phospholipid plasmalogen synthesis for virus production ( Jean Beltran et al, 2018 ). Peroxisomes also display heterogeneity in the same cell.…”

Temporal dynamics of protein complex formation and dissociation during human cytomegalovirus infection

“…RAW files containing MS/MS spectra collected in PRM mode were imported into Skyline to extract product ion chromatograms (XICs) and calculate peak areas. A human and herpesvirus peptide spectral library was generated using Skyline (v4.0) from DDA MS analyses of Murray et al 83 and Jean Beltran et al 94 . The list of peptides was filtered based on ion intensity and peak area reproducibility across replicates.…”