Abstract

Many viruses activate cellular autophagy in infected cells to facilitate their replication. Recently, we identified an interferon (IFN)-stimulated gene (ISG) Tudor domain containing 7 (TDRD7), which inhibits viral replication by blocking autophagy pathway. Here, we present a molecular mechanism for TDRD7 action and its relative contribution to protection against viral pathogenesis. TDRD7 inhibited the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a kinase required for initiating autophagy. Mechanistically, TDRD7 interacted directly with AMPK in the cytosolic compartment. Domain-mapping analyses revealed C-terminal Tudor domain of TDRD7 interacted with auto-inhibitory domain of AMPK. Deletion of Tudor domains abolished anti-AMPK and antiviral activities of TDRD7. We evaluated physiological relevance of TDRD7 function against viral replication using newly engineered TDRD7 knockout mice and the derived primary cells. TDRD7 knockout primary cells displayed increased AMPK activation, which led to a higher viral load. Subsequently, TDRD7 knockout mice showed enhanced susceptibility upon intranasal Sendai virus infection. Therefore, our study revealed a new antiviral function of IFN, mediated by TDRD7-AMPK, inhibiting viral replication and pathogenesis.

Document Type

Article

Publication Date

9-2023

Notes/Citation Information

Copyright © 2023 Chakravarty et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Digital Object Identifier (DOI)

https://doi.org/10.1128/MBIO.00611-23

Funding Information

HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID): AI155545, Saurabh Chattopadhyay.

HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) AI165521. Saurabh Chattopadhyay.

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