AutophagyApr 22, 2026

CRISPR screen finds a lysosome protein that helps block PRRS virus infection

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 23, 2026

Abstract

LAPTM4A is identified as a critical antiviral factor in the lysosomal pathway associated with the replication of porcine reproductive and respiratory syndrome virus (PRRSV).

PRRSV manipulates host cell processes, notably autophagy and lysosomal function, to enhance its replication.
A CRISPR-Cas9 knockout screen targeting 1,332 genes revealed LAPTM4A's role in the lysosomal pathway.
PRRSV glycoprotein GP5 interacts with LAPTM4A, leading to its degradation via a mechanism involving specific ubiquitination.
The degradation of LAPTM4A activates a signaling cascade that initiates autophagy and disrupts lysosome-related gene expression.
Incomplete autophagic flux resulting from LAPTM4A degradation is associated with increased viral replication.
LAPTM4A also plays a role in maintaining lysosomal function and antiviral defense against various RNA viruses.

Simplified

Porcine reproductive and respiratory syndrome virus (PRRSV) manipulates host intracellular processes, particularly macroautophagy/autophagy and lysosomal function, to facilitate its replication and spread. However, the precise host factors and molecular mechanisms by which PRRSV remodels the autophagy-lysosome axis remain poorly defined. Here, we performed a CRISPR-Cas9 knockout screen targeting 1,332 genes involved in protein degradation, metabolism, and vesicular trafficking, and identified LAPTM4A (lysosomal protein transmembrane 4 alpha) as a critical antiviral factor involved in the lysosomal pathway. A yeast two-hybrid screen identified LAPTM4A as an interactor of PRRSV GP5 (glycoprotein 5). Mechanistically, GP5 recruits the E3 ubiquitin ligase NEDD4 and the autophagy receptor SQSTM1/p62 to promote K63-linked polyubiquitination of LAPTM4A, leading to its autophagic degradation. This selective degradation activates the AMPK-ULK1-MAP1LC3/LC3 signaling cascade, initiating autophagy while facilitating MTOR-lysosome colocalization, thereby suppressing TFEB nuclear translocation and transcription of lysosome-related genes. The resulting incomplete autophagic flux enhances viral replication. Additionally, in terms of host defense, LAPTM4A maintains lysosomal homeostasis by restraining excessive autophagy through AMPK-ULK1-LC3 signaling and promoting TFEB-dependent lysosomal gene expression by impairing the binding of RPTOR/raptor to MTOR, thus providing broad antiviral protection against multiple RNA viruses. Collectively, our findings identify LAPTM4A as a central regulator of lysosome-autophagy homeostasis and reveal a viral strategy that dismantles this defense axis to facilitate infection.

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CRISPR screen finds a lysosome protein that helps block PRRS virus infection

Abstract

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