IRGM Is a Common Target of RNA Viruses that Subvert the Autophagy Network

Abstract

Autophagy is a conserved degradative pathway used as a host defense mechanism against intracellular pathogens. However, several viruses can evade or subvert autophagy to insure their own replication. Nevertheless, the molecular details of viral interaction with autophagy remain largely unknown. We have determined the ability of 83 proteins of several families of RNA viruses (Paramyxoviridae, Flaviviridae, Orthomyxoviridae, Retroviridae and Togaviridae), to interact with 44 human autophagy-associated proteins using yeast two-hybrid and bioinformatic analysis. We found that the autophagy network is highly targeted by RNA viruses. Although central to autophagy, targeted proteins have also a high number of connections with proteins of other cellular functions. Interestingly, immunity-associated GTPase family M (IRGM), the most targeted protein, was found to interact with the autophagy-associated proteins ATG5, ATG10, MAP1CL3C and SH3GLB1. Strikingly, reduction of IRGM expression using small interfering RNA impairs both Measles virus (MeV), Hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1)-induced autophagy and viral particle production. Moreover we found that the expression of IRGM-interacting MeV-C, HCV-NS3 or HIV-NEF proteins per se is sufficient to induce autophagy, through an IRGM dependent pathway. Our work reveals an unexpected role of IRGM in virus-induced autophagy and suggests that several different families of RNA viruses may use common strategies to manipulate autophagy to improve viral infectivity.

The Emerging Importance of Autophagy in Pulmonary Diseases

“…76 After HIV, TB is the lead ing infectious cause of death worldwide. Interestingly, HIV also manipulates autophagy to improve viral infec tivity, 77 and a common target of RNA viruses is IRGM . 77 Together, these findings underscore the importance of host autophagy in orchestrating successful antimicrobial responses to mycobacteria.…”

“…Interestingly, HIV also manipulates autophagy to improve viral infec tivity, 77 and a common target of RNA viruses is IRGM . 77 Together, these findings underscore the importance of host autophagy in orchestrating successful antimicrobial responses to mycobacteria. Reports have identifi ed cases of totally drug-resistant TB in India with fears that totally drug-resistant TB will spread worldwide.…”

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

“…Nevertheless, Singh et al (13,14) showed that human IRGM stimulates autophagy and proposed that IRGM localized to mitochondria, aiding mitochondrial fission, an event that was suggested to be required for IRGM-mediated autophagic restriction of mycobacteria. In relation to viruses, Grégoire et al (15) generated two-hybrid-based protein interaction maps and found that human IRGM was highly targeted by RNA viral proteins (from HCV, measles virus, and HIV-1) and interacted with autophagy components, thereby suggesting that IRGM is manipulated for promotion of virus replication.…”

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

“…Previous work has attributed the bacterial susceptibility in Irgm1-deficient mice to defective processing of bacteria-containing phagosomes in macrophages and other cells (5,15,(25)(26)(27). That reduced capacity to manifest IFN-␥-induced killing of S. typhimurium and Mycobacterium tuberculosis has been further linked to altered autophagic function in Irgm1-deficient macrophages (15,20,21,(27)(28)(29)(30). Impaired autophagy ostensibly leads to a reduced capacity to restrict bacterial growth, increased inflammation, and ultimately death of the host, although these linkages have not been formally established.…”