# NPRL2 restricts porcine reproductive and respiratory syndrome virus replication by targeting viral Nsp1α for autophagic degradation

## TL;DR

NPRL2 helps fight a virus in pigs by targeting a key viral protein for destruction through a cellular process called autophagy.

## Contribution

NPRL2 is a new host factor that restricts PRRSV replication by ubiquitinating and degrading viral Nsp1α via autophagy.

## Key findings

- NPRL2 interacts with PRRSV Nsp1α to inhibit viral replication.
- NPRL2 mediates K63-linked ubiquitination of Nsp1α at lysine 150.
- NPRL2 recruits autophagic machinery to degrade Nsp1α.

## Abstract

Host factors that directly target viral immune antagonists are crucial for antiviral defense. In this study, we identify NPRL2 as a novel host restriction factor that directly interacts with the porcine reproductive and respiratory syndrome virus (PRRSV) protein Nsp1α, a key viral virulence factor. This interaction is mediated by the C-terminal domain of NPRL2 and the PCPα domain of Nsp1α. Functional studies demonstrated that NPRL2 overexpression inhibits PRRSV replication, while its knockdown enhanced viral propagation. Mechanistically, NPRL2 acts as a bridge, mediating K63-linked ubiquitination of Nsp1α at lysine 150 and subsequently recruiting the autophagic machinery for its degradation. This process was confirmed by monitoring LC3-II conversion and autophagic flux. Our findings reveal a precise mechanism by which NPRL2 antagonizes PRRSV by targeting a critical viral protein for autophagic degradation, highlighting the therapeutic potential of harnessing the host’s ubiquitin–autophagy pathway to combat viral infections.