Modulation of viral replication, autophagy and apoptosis by induction and mutual regulation of transcription factors EB and E3 during coronavirus infection

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Abstract Viral invasion of and replication in cells pose a significant impact on the structure and function of lysosomes. By sensing changes in the lysosome status, cascades of cellular responses are triggered to maintain the lysosomal homeostasis. Two key regulators, transcription factors EB (TFEB) and E3 (TFE3), play essential regulatory roles in these processes by shuttling between the cytoplasm and the nucleus. In this study, we report that infection of cells and/or chickens by gammacoronavirus infectious bronchitis virus (IBV), human betacoronavirus OC43 (HCoV-OC43), and alphacoronavirus porcine epidemic diarrhea virus (PEDV) upregulates the expression of TFEB/TFE3 as well as their downstream targets, and induces the lysosomal stress response. Knockdown of TFE3 alone or together with TFEB demonstrated a pronounced role played by TFE3 in regulating viral replication, virus-induced autophagy and apoptosis in cells infected with these viruses, and a synergistic effect of TFEB and TFE3 in regulation of these processes in cells infected with IBV and HCoV-OC43. Inhibition of the biosynthetic secretory pathway with brefeldin A (BFA) demonstrated that the release of HCoV-OC43 is mainly via the lysosomal pathway. This study provides novel insights into the functional roles of the lysosomal biogenesis and stress response in coronavirus replication and virus-host interactions. Importance In recent years, more and more studies have shown that lysosomes function more than just as a recycling bin, they also play an important role as a hub for energy and signal transduction, autophagy regulation, and many physiological or pathological processes. This study showed that coronavirus infection activates lysosomal stress responses. As two transcription factors that regulate lysosomal biogenesis, TFEB and TFE3 regulate autophagy and apoptosis during the coronavirus replication cycle. In addition, it has been found that HCoV-OC43 releases viral particles through the lysosomal pathway, which may provide a new reference for the treatment of mitigating coronavirus infection.

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