[F31] Regulation of HSV-1 Latency by hnRNPK
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-08-14
Importo max: $39,780
Paese: US
Descrizione
Project Summary/Abstract
Herpes Simplex Virus-1 (HSV-1) infects over 50% of individuals in the United States, establishing life-long
latent infection in post-mitotic peripheral neurons. Viral reactivation can lead to symptomatic lytic infection in
the epithelial mucosa, eye or central nervous system, leading to death in some individuals. During HSV-1
latency, the viral genome associates with host histones and is enriched with histone post-translational
modifications forming heterochromatin. It is thought that latency is established by and maintained via
association of the viral genome with heterochromatin. Our lab has shown that the viral genome associates with
a type of facultative heterochromatin during early latency establishment known as Polycomb silencing. This is
initiated and maintained by a mono-ubiquitin modification of H2AK119 (H2Aub1) by the Polycomb Repressive
Complex 1 (PRC1). Importantly, the deposition of the H2Aub1 mark on the viral genome by PRC1 increases
the ability of the latent viral genome to reactivate from latency. However, it is unknown how PRC1 is recruited
to the viral genome during HSV-1 infection.
In de novo gene silencing in pluripotent cells, cellular protein hnRNPK can act as a scaffolding protein,
interacting with both PRC1-associated proteins and lncRNA, to facilitate H2Aub1 deposition on target loci. The
lncRNA interacting with hnRNPK is largely responsible for determining the loci that are targeted for H2Aub1
deposition and silencing by increasing the local concentration of PRC1 at chromosomal regions. This is of
particular interest, as my preliminary data indicate that hnRNPK interacts with a lncRNA transcribed from the
viral genome, the Latency Associated Transcript (LAT), during infection of neurons. Additionally, my data show
that hnRNPK depletion prior to HSV-1 infection reduces the ability of the latent viral genome to reactivate from
latency, mirroring the effect observed following PRC1 inhibition. Here, I will investigate the mechanism by
which hnRNPK promotes HSV-1 reactivation-competent latency. Specifically, I will determine the contribution of
hnRNPK to H2Aub1 deposition on the viral genome (Aim 1) and determine the consequence of LAT on
hnRNPK recruitment (Aim 2). Taken together, my central hypothesis is that in hnRNPK facilitates Polycomb
silencing by interacting with PRC1-associated proteins and the LAT, to mediate the deposition of H2Aub1 on
the viral genome and promote a form of gene silencing that is capable of later undergoing reactivation. This
would be significant, as it would demonstrate an active mechanism by which HSV-1 modulates the nature of
gene silencing during latency to enable reactivation competent, facultative heterochromatin formation on the
viral genome. Ultimately, by studying the mechanisms and consequence on H2Aub1 formation on the latent
viral genome may identify new therapeutic targets to prevent reactivation from occurring.
Istituzione: UNIVERSITY OF VIRGINIA
PI: James M Boehlke
Progetto: 1F31AI202519-01
Settori: National Institute of Allergy and Infectious Diseases
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