Saud, R. | bioRxiv Science

bioRxiv2026

Herpes simplex virus 1 subverts the mitochondrial network to support the infection: A lesson on mitochondrial versatility

Herpes simplex virus 1 (HSV-1) infects approximately 67% of the population worldwide. It establishes lifelong reservoirs in sensory neurons and has been linked to several diseases including neuronal dysfunction. Disruption of mitochondrial homeostasis is a hallmark of HSV-1 infection, however a molecular understanding of these changes and their significance is not yet well defined. HSV-1 infection causes a UL12.5-dependent inhibition of mitochondrial biogenesis through the loss of mitochondrial DNA and mitochondrial transcription factors, PGC-1 (peroxisome proliferator-activated receptor-gamma co-activator) and TFAM (mitochondrial transcription factor). Conversely, UL12.5-independent mechanisms inhibit mitochondrial fusion by activating the OMA1 metallopeptidase that cleaves the inner mitochondrial membrane fusion protein OPA1 (optic atrophy protein 1) and by down-modulating the outer mitochondrial membrane fusion protein MFN2 (mitofusin 2). This inhibition of fusion results in a smaller mitochondrial network that clusters to perinuclear regions, likely supplying energy for viral replication and envelopment. The inner mitochondrial membrane protein TIM23 is also down-modulated during infection in a UL12.5-independent mechanism. Failure of the virus to promote these changes negatively impacts the infection. Despite these changes, mitochondria are protected from mitophagy due to the viral-induced degradation of several mitophagy adaptor proteins, whereby damaged mitochondrial components, including mitochondrial DNA, are extruded via extracellular vesicles. These mitochondrial changes still support functions necessary for HSV-1 infection. Basal cell respiration is preserved, while spare respiratory capacity and extracellular acidification rates increase, indicating glycolytic activity. Mitochondrial membrane potential is also preserved. Overall, our studies provide mechanistic insight into how HSV-1 impacts mitochondria, which could contribute to viral pathogenesis.

microbiology↗

bioRxiv2022

SARS-CoV-2 harnesses host translational shutoff and autophagy to optimize virus yields: The role of the envelope (E) protein

The SARS-CoV-2 virion is composed of four structural proteins: spike (S), nucleocapsid (N), membrane (M), and envelope (E). E spans the membrane a single time and is the smallest, yet most enigmatic of the structural proteins. E is conserved among coronaviruses and has an essential role in virus-mediated pathogenesis. We found that ectopic expression of E had deleterious effects on the host cell as it activated stress responses, leading to phosphorylation of the translation initiation factor eIF2 and LC3 lipidation that resulted in host translational shutoff. During infection E is highly expressed although only a small fraction is incorporated into virions, suggesting that E activity is regulated and harnessed by the virus to its benefit. In support of this, we found that the {gamma}1 34.5 protein of herpes simplex virus 1 (HSV-1) prevented deleterious effects of E on the host cell and allowed for E protein accumulation. This observation prompted us to investigate whether other SARS-CoV-2 structural proteins regulate E. We found that the N and M proteins enabled E protein accumulation, whereas S prevented E accumulation. While {gamma}1 34.5 protein prevented deleterious effects of E on the host cells, it had a negative effect on SARS-CoV-2 replication. This negative effect of {gamma}1 34.5 was most likely associated with failure of SARS-CoV-2 to divert the translational machinery and with deregulation of autophagy pathways. Overall, our data suggest that SARS-CoV-2 causes stress responses and subjugates these pathways, including host protein synthesis (phosphorylated eIF2) and autophagy, to support optimal virus production. ImportanceIn 2020, a new {beta}-coronavirus, SARS-CoV-2, entered the human population that has caused a pandemic resulting in 6 million deaths worldwide. Although closely related to SARS-CoV, the mechanisms of SARS-CoV-2 pathogenesis are not fully understood. We found that ectopic expression of the SARS-CoV-2 E protein had detrimental effects on the host cell, causing metabolic alterations including shutoff of protein synthesis and mobilization of cellular resources through autophagy activation. Co-expression of E with viral proteins known to subvert host antiviral responses such as autophagy and translational inhibition, either from SARS-CoV-2 or from heterologous viruses increased cell survival and E protein accumulation. However, such factors were found to negatively impact SARS-CoV-2 infection, as autophagy contributes to formation of viral membrane factories, and translational control offers an advantage for viral gene expression. Overall, SARS-CoV-2 has evolved mechanisms to harness host functions that are essential for virus replication.

microbiology↗