TRIM69 Suppresses the Cellular AMPK Pathway to Inhibit Viral Replication

Interferon-stimulated genes (ISGs) mount an antiviral defense by targeting both viral components and cellular pathways required for infection. Here, we show that the interferon- and virus-inducible antiviral factor TRIM69 suppresses cellular AMP-activated protein kinase (AMPK) signaling and restricts replication of both RNA and DNA viruses. Ectopic expression of TRIM69 inhibited Sendai virus (SeV)-induced autophagy and suppressed phosphorylation of AMPK and its downstream target, ULK1, in response to viral infection and nutrient deprivation. Consistent with inhibition of this proviral AMPK signaling pathway, TRIM69 expression strongly restricted replication of paramyxoviruses and pneumoviruses, including SeV, respiratory syncytial virus (RSV), human parainfluenza virus type 3 (HPIV3), and herpesviruses, e.g., herpes simplex virus type 1 (HSV-1). Consistent with these findings, knockdown of endogenous TRIM69 enhanced viral replication, demonstrating a physiological antiviral role for TRIM69. In addition to suppressing viral replication, TRIM69 supported the expression of antiviral genes, including IFNB1, IFIT2, and IFIT3, suggesting amplification of the innate antiviral signaling. Together, these findings identify TRIM69 as a broad antiviral ISG that targets the cellular AMPK pathway and contributes to host innate immune responses against viruses.