Biology subjects

Lewis, H. C.

Publications and source records attributed to Lewis, H. C..

4 recordsLinked to original sources

bioRxiv2024

Human cytomegalovirus induces neuronal gene expression for viral maturation

Viral invasion of the host cell causes some of the most dramatic changes in biology. Human cytomegalovirus (HCMV) extensively remodels host cells, altering nuclear shape and generating a cytoplasmic viral-induced assembly compartment (vIAC). How these striking morphology changes take place in the context of host gene regulation is still emerging. Here, we discovered that histone variant macroH2A1 is essential for producing infectious progeny. Because virion maturation and cellular remodeling are closely linked processes, we investigated structural changes in the host cell upon HCMV infection. We discovered that macroH2A1 is necessary for HCMV-induced reorganization of the host nucleus, cytoskeleton, and endoplasmic reticulum. Furthermore, using RNA-seq we found that while all viral genes were highly expressed in the absence of macroH2A1, many HCMV-induced host genes were not. Remarkably, hundreds of these HCMV-induced macroH2A1-dependent host genes are associated with neuronal synapse formation and vesicle trafficking. Knock-down of these HCMV-induced neuronal genes during infection resulted in malformed vIACs and smaller plaques, establishing their importance to HCMV infection. Together, our findings demonstrate that HCMV manipulates host gene expression by hijacking a dormant neuronal secretory pathway for efficient virion maturation.

microbiology↗

bioRxiv2023

Chemobiosis reveals tardigrade tun formation is dependent on reversible cysteine oxidation

Tardigrades, commonly known as waterbears, are eight-legged microscopic invertebrates renowned for their ability to withstand extreme stressors, including high osmotic pressure, freezing temperatures, and complete desiccation. Limb retraction and expelling their internal water stores results in the tun state, greatly increasing their ability to survive. Emergence from the tun state and/or activity regain follows stress removal, where resumption of life cycle occurs as if stasis never occurred. However, the mechanism(s) through which tardigrades initiate tun formation is yet to be uncovered. Herein, we use chemobiosis to demonstrate that tardigrade tun formation is mediated by reactive oxygen species (ROS). We further reveal that tuns are dependent on reversible cysteine oxidation, and that this reversible cysteine oxidation is facilitated by the release of intracellular reactive oxygen species (ROS). We provide the first empirical evidence of chemobiosis and map the initiation and survival of tardigrades via osmobiosis, chemobiosis, and cryobiosis. In vivo electron paramagnetic spectrometry suggests an intracellular release of reactive oxygen species following stress induction; when this release is quenched through the application of exogenous antioxidants, the tardigrades can no longer survive osmotic stress. Together, this work suggests a conserved dependence of reversible cysteine oxidation across distinct tardigrade cryptobioses.

biochemistry↗

bioRxiv2022

HSV-1 exploits host heterochromatin for egress

Herpes simplex virus (HSV-1) progeny form in the nucleus and must exit to successfully infect other cells. These newly formed viral capsids navigate the complex chromatin architecture of the nucleus to reach the inner nuclear membrane and egress. Here, we demonstrate by transmission electron microscopy (TEM) that HSV-1 capsids traverse dense heterochromatin in the nuclear periphery to reach the inner nuclear membrane. We found that this heterochromatin is dependent on the specific chromatin marks of trimethylation on histone H3 lysine 27 (H3K27me3) and the histone variant macroH2A1. Through chromatin profiling over the course of infection, we revealed massive host genomic regions bound by macroH2A1 and H3K27me3 that correlate with decreased host transcription in active compartments. This indicates the formation of new heterochromatin during infection. We found that loss of these markers resulted in significantly lower viral titers but did not impact viral genome or protein accumulation. Strikingly, we discovered by TEM that loss of macroH2A1 or H3K27me3 resulted in nuclear trapping of viral capsids. Thus, our work demonstrates that HSV-1 takes advantage of the dynamic nature of host heterochromatin formation during infection for efficient viral egress.

microbiology↗

bioRxiv2020

A viral histone-like protein exploits H1-HMGB1 antagonism for chromatin invasion

Virus infection necessarily requires redirecting cellular resources towards viral progeny production. Adenovirus encodes the histone-like protein VII that causes catastrophic global reorganization of host chromatin to promote virus infection. Protein VII recruits the family of high mobility group box (HMGB) proteins to chromatin along with the histone chaperone SET. As a consequence of this recruitment, we find that protein VII causes chromatin-depletion of several linker histone H1 isoforms. The relationship between linker histone H1 and the functionally opposite HMGB proteins is critical for higher order chromatin structure. However, the physiological consequences of perturbing this relationship are largely unknown. Here, we employ complementary systems in Saccharomyces cerevisiae and human cells to demonstrate that adenovirus protein VII disrupts the H1-HMGB balance to obstruct the cell cycle. We find that protein VII causes an accumulation of G2/M cells both in yeast and human systems, underscoring the high conservation of this chromatin vulnerability. In contrast, adenovirus E1A and E1B proteins are well-established to override cell cycle regulation and promote transformation of human cells. Strikingly, we find that protein VII obstructs the cell cycle even in the presence of E1A and E1B, suggesting that protein VII-directed cell cycle disruption ensures host resources are directed towards viral proliferation during infection. Together, our results demonstrate that protein VII targets H1-HMGB1 antagonism to obstruct cell cycle progression, revealing an unexpected chromatin vulnerability exploited for viral benefit.

microbiology↗