# YAP Inhibits HIV-1 transcription and promotes HIV-1 latency by regulating E3 ubiquitin ligase UHRF1 mediated tat degradation

## TL;DR

This study shows that YAP, a host protein, helps keep HIV-1 in a dormant state by causing the breakdown of a key viral protein called Tat.

## Contribution

The study identifies YAP as a novel regulator of HIV-1 latency through its role in Tat ubiquitination and degradation.

## Key findings

- YAP inhibits HIV-1 transcription by promoting ubiquitination and proteasomal degradation of Tat.
- The YAP TAD domain recruits UHRF1 to mediate Tat ubiquitination.
- Lysine residues K28, K29, and K41 on Tat are critical for ubiquitination and degradation.

## Abstract

The latency of human immunodeficiency virus type 1 (HIV-1) is a major barrier to achieving an HIV-1 cure, as antiretroviral therapy does not target the latent virus. Virus-host interactions play an essential role in various stages of the HIV-1 lifecycle. Exploring the interaction between host factors and HIV-1 infection is critical for developing new HIV-1 treatment strategies. Yes-associated protein (YAP) is a key co-transcription factor in the Hippo signaling pathway, which regulates the occurrence and development of various diseases, including cellular metabolism, cancer, immunity, and viral infection. In this study, we first confirmed that YAP gene expression in patients with acquired immune deficiency syndrome (AIDS) was significantly lower than that in the healthy control group, as determined using the GEO2R online tool. Furthermore, YAP was identified as a negative regulator of HIV-1 transcription by mediating K33- and K48-linked ubiquitination and proteasomal degradation of Tat. Here, we further confirmed that the YAP TAD domain recruited ubiquitin-like with PHD and RING finger domain 1 (UHRF1) to mediate Tat’s ubiquitination and degradation by the screening of the BioGRID database combined with IP-MS analysis. The conserved lysine residues K28, K29, and K41 on Tat were critical acceptor sites for ubiquitination and proteasomal degradation. Our findings revealed that YAP promotes the suppression of HIV-1 transcription and the maintenance of HIV-1 latency, providing novel insights into virus-host interactions for regulating HIV-1 latency.

HIV-1 latency, a dormant state in which the virus remains in cells unnoticed by antiretroviral therapy, is the reason why HIV-1 is still incurable. New HIV-1 therapeutics depend on an understanding of how host factors regulate the virus. Here, we focus on Yes-associated protein (YAP), which controls cellular functions such as viral infection and immunology. We found that YAP inhibits HIV-1 by specifically targeting the viral protein Tat, which is essential for HIV-1 replication. Especially, Tat is destroyed when YAP enhances Tat ubiquitination with the help of host protein UHRF1. The three crucial locations on Tat (K28, K29, and K41) have been certified to be crucial for Tat ubiquitination and subsequent degradation. Our research reveals a new mechanism by which YAP maintains HIV-1 latency and highlights host-virus interactions as promising targets for future HIV-1 cure.