Henan Agricultural University's Chu Beibei team has made important progress in the research of alpha herpes virus infection

Recently, Professor Chu Beibei’s team from the School of Veterinary Medicine of Henan Agricultural University has made important progress in the research of alpha herpes virus infection.
The study found that USP14 deubiquitinated VP16 after binding to the pseudorabies virus (PRV) VP16 protein in the early stage of infection.
, To ensure early gene transcription required for virus replication
.

Inhibition of USP14 can promote autophagy induced by ER stress, and then degrade through SQSTM1/p62-mediated selective autophagy pathway
.

Herpes virus is a double-stranded DNA virus with an envelope, divided into three subfamilies: alpha herpes virus, beta herpes virus and gamma herpes virus
.

Alpha-herpes viruses include Herpes simplex virus type 1/2 (HSV-1/2) that can infect humans, Varicella-zoster virus (VZV), and pseudorabies that infect animals Virus (Pseudorabies virus, PRV), Duck enteritis virus (Duck enteritis virus, DEV)
.

Alpha herpes has a wide range of hosts and has a unique latent-reactivation infection mechanism
.

Over 3.
7 billion people under the age of 50 are infected with HSV-1 worldwide, and 417 million people between the ages of 17 and 49 are infected with HSV-2
.

There is no effective vaccine for alpha herpes virus in the world
.

Ubiquitin-specific proteases (USPs) are the largest subfamily of deubiquitinating enzymes and play important functions in immune and infectious diseases
.

In order to study the role of USP in alpha herpesvirus replication, the authors evaluated the effects of 13 USP inhibitors on PRV replication
.

The results showed that 13 kinds of USP inhibitors can inhibit PRV proliferation, of which the USP14 inhibitor b-AP15 has the most significant inhibitory effect.
At the same time, knocking out USP14 can also inhibit PRV proliferation (Figure 1)
.

Figure 1 Knockout of USP14 inhibits PRV proliferation The author further analyzed the specific molecular mechanism of inhibiting USP14 affecting PRV proliferation
.

The results of the study show that USP14 directly interacts with the VP16 envelope protein involved in the immediate early gene and early gene transcription of PRV in the early stage of infection to deubiquitinate VP16, thereby stabilizing VP16 and benefiting PRV replication
.

Inhibition of USP14 promotes K63-linked ubiquitination modification and protein degradation of lysine 168 of VP16
.

However, this protein degradation does not depend on the ubiquitin-proteasome system, but on the autophagy pathway caused by endoplasmic reticulum stress
.

Ubiquitinated VP16 binds to the selective autophagy receptor molecule SQSTM1 and is degraded by the autophagy-lysosomal system
.

In addition, USP14 inhibitors have better effects on preventing and treating PRV infection in mice
.

This study clarified the molecular mechanism of inhibiting the selective autophagy degradation of alpha herpes virus VP16 by inhibiting USP14, and provided a new drug target for the treatment of alpha herpes virus infection (Figure 2)
.

Figure 2 Inhibition of USP14 influences alphaherpesvirus replication pattern.
The research results were published online in the internationally renowned journal "Autophagy" with a research paper entitled "Inhibition of USP14 influences alphaherpesvirus proliferation by degrading viral VP16 protein via ER stress-triggered selective autophagy" ( IF=16.
016)
.

Chu Beibei is the corresponding author, and Ming Shengli of Basic Veterinary Medicine of Henan Agricultural University, Dr.
Zhang Shuang and Master Wang Qi are the co-first authors of this article
.

This research was supported by the National Natural Science Foundation of China, the Natural Science Foundation of Henan Province and the Outstanding Talents Project of Henan Agricultural University
.

Link to the paper: https://doi.
org/10.
1080/15548627.
2021.
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