# PINLYP-mediated phospholipid metabolism reprogramming contributes to chronic herpesvirus infection

## TL;DR

This study shows that the host protein PINLYP helps suppress herpesvirus reactivation by altering phospholipid metabolism, offering a new target for controlling chronic infections.

## Contribution

The study identifies PINLYP as a host factor hijacked by KSHV to regulate phospholipid metabolism and promote viral latency.

## Key findings

- PINLYP deficiency increases cPLA2α activity and KSHV lytic reactivation.
- PINLYP regulates ACSL5 expression and TAG biosynthesis to suppress viral reactivation.
- Inhibiting ACSL5 or TAG production reverses the effects of PINLYP deficiency.

## Abstract

Many viruses alter the phospholipid metabolism to benefit their own life cycles. It is unclear whether the host or the virus is driving phospholipid metabolism reprogramming, and how virus infections are affected by the metabolic status. Here we report that phospholipase A2 inhibitor and LY6/PLAUR domain-containing protein (PINLYP) inhibits Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic reactivation by remodeling phospholipid metabolism and especially triacylglycerol (TAG) biosynthesis. PINLYP deficiency led to increased phospholipase cPLA2α activity, cPLA2α-mediated AKT phosphorylation, and KSHV lytic reactivation. Analyses of RNA-seq and lipidomics reveal that PINLYP regulates long-chain fatty acid CoA ligase ACSL5 expression and TAG production. The inhibition of ACSL5 activity or TAG biosynthesis suppresses AKT phosphorylation and KSHV lytic reactivation, restoring the phenotype of PINLYP deficiency. This finding underscores the pivotal role of PINLYP in remodeling phospholipid metabolism and promoting viral latency, which sheds new light on how phospholipid metabolism is regulated by herpesvirus and provides a potential target for controlling chronic herpesvirus infection.

Many viruses change the host phospholipid metabolism for their own life cycles. However, it remains unknown for the underlying mechanism by which phospholipid metabolism reprogramming is driven by the host or the virus. Here we report that KSHV infection induces the expression of phospholipase A2 inhibitor and LY6/PLAUR domain-containing protein PINLYP, which in turn remodels phospholipid metabolism and particularly TAG biosynthesis in KSHV latently infected cells, ultimately leading to the suppression of KSHV lytic reactivation. Our results reveal that KSHV hijacks the host factor PINLYP to change phospholipid metabolism for benefiting its latent infection, providing a new target for controlling herpesvirus infection.