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Differential regulation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is considered the rate-limiting enzyme of the cholesterol biosynthesis pathway, has been reported in case of infection with many viruses. In our study, we have found that influenza virus infection decreases total cellular cholesterol level which is directly related to the downregulation of HMGCR protein. We found that HMGCR is degraded through ubiquitination and proteasomal-mediated pathway upon viral infection. Upregulation of Autocrine Motility Factor Receptor (AMFR), which is an E3-ubiquitin ligase of HMGCR, was also observed. Furthermore, knockdown of AMFR inhibits ubiquitination of HMGCR and also leads to inactivation of the innate immunity components TANK-binding kinase 1 (TBK1) and Interferon regulatory factor 3 (IRF3). Our study is the first to show the role of HMGCR and AMFR in influenza virus infection and reveals that AMFR plays a crucial role in the downregulation of HMGCR and the activation of innate immunity following influenza virus infection. [Display omitted] • Influenza virus infection decreases total cellular cholesterol in A549 cells. • HMGCR, the rate-limiting enzyme of the cholesterol biosynthesis pathway is down-regulated upon influenza virus infection. • AMFR leads to ubiquitination and proteasomal-mediated degradation of HMGCR following influenza virus infection. • AMFR activates STING-mediated innate immunity response following influenza virus infection. [ABSTRACT FROM AUTHOR]