PRRSV-induced glucose-6-phosphate transporter promotes viral replication by suppressing type I interferon transcription.

Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) leads to significant economic losses for the global swine industry. Screening and identification of PRRSV-regulated host proteins, followed by the development of long-acting anti-PRRSV therapeutics targeting these genetically stable host factors, represents a mainstream research direction in this field. Glucose-6-phosphate transporter (G6PT) is a core regulator of glucose uptake. However, its role in PRRSV infection remains unknown. Here, we report for the first time that PRRSV infection significantly upregulated the expression of G6PT in MARC-145 cells, a monkey kidney cell line, and in porcine alveolar macrophage (PAM)-Tang, a PAM-derived immortalized cell line. Functionally, overexpression of G6PT facilitated PRRSV replication, while knockdown of G6PT inhibited PRRSV replication. These findings indicated that G6PT contributed to efficient PRRSV propagation. Mechanistically, G6PT suppressed retinoic acid-inducible gene I (RIG-I)- and Toll-like receptor 3 (TLR3)-mediated type I interferon transcription in a manner independent of its canonical G6P transport activity. Furthermore, G6PT overexpression upregulated key glycolytic enzymes, including hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). In conclusion, we propose that PRRSV hijacks G6PT to promote its replication by suppressing innate immunity and enhancing aerobic glycolysis, identifying G6PT as a potential novel target for anti-PRRSV drug development.