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Review
. 2021 Oct 22:11:743780.
doi: 10.3389/fonc.2021.743780. eCollection 2021.

Autophagy Modulation by Viral Infections Influences Tumor Development

Lucas Leonardi  1   2 , Sophie Sibéril  1   2 , Marco Alifano  1   3 , Isabelle Cremer  1   2 , Pierre-Emmanuel Joubert  1   2
Affiliations
Review

Autophagy Modulation by Viral Infections Influences Tumor Development

Lucas Leonardi et al. Front Oncol. .

Abstract

Autophagy is a self-degradative process important for balancing cellular homeostasis at critical times in development and/or in response to nutrient stress. This is particularly relevant in tumor model in which autophagy has been demonstrated to have an important impact on tumor behavior. In one hand, autophagy limits tumor transformation of precancerous cells in early stage, and in the other hand, it favors the survival, proliferation, metastasis, and resistance to antitumor therapies in more advanced tumors. This catabolic machinery can be induced by an important variety of extra- and intracellular stimuli. For instance, viral infection has often been associated to autophagic modulation, and the role of autophagy in virus replication differs according to the virus studied. In the context of tumor development, virus-modulated autophagy can have an important impact on tumor cells' fate. Extensive analyses have shed light on the molecular and/or functional complex mechanisms by which virus-modulated autophagy influences precancerous or tumor cell development. This review includes an overview of discoveries describing the repercussions of an autophagy perturbation during viral infections on tumor behavior.

Keywords: autophagy; immunity; oncogenic virus; oncolytic virus; tumor development and progression; tumor resistance; tumorigenesis; viral infection.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Autophagy machinery and its modulation by viruses. Beclin-1/PI3KC3 complex activation, which is regulated by different mechanisms including the ULK1/2 complex and mTORC1 complex, results in the induction of an autophagic vesicle, which is characterized by a double-membrane, named autophagosome. Two ubiquitin-like systems are essential for autophagosome formation. In the first, autophagy-related gene-12 (Atg12) is conjugated to Atg5, together forming a complex with Atg16L1, which decorates the outer membrane of the phagophore. Microtubule-associated protein 1 light chain-3 (LC3, also known as Atg8) constitutes the second ubiquitin-like system and conjugates phosphatidylethanolamine (PE) at the outer and inner autophagosomal membrane. Unlike the Atg12/Atg5/Atg16L1 complex that is recycled by the protease Atg4, the LC3-PE (referred to LC3-II) remains associated with the inner membrane of autophagosome. The incorporation of phospholipid into the autophagosome membrane is essential for its elongation and regulates the membrane transport system. Autophagosome maturation is characterized by the formation of an autolysosome, the product of fusion with the lysosome. Viruses activate or inhibit autophagy at several step, as indicated on the figure. VSV, Vesical Stomatitis Virus; SeV, Sendai Virus; MeV, Measles Virus; HIV, Human Immunodeficiency Virus; CRads, Conditionally Replicating Adenoviruses; HSV, Herpes Simplex Virus; KSHV, Kaposi’s Sarcoma-associated Herpesvirus; MHV, Mouse Hepatitis Virus; HCMV, Human Cytomegalovirus; MCPyV, Merkel Cell Polyomavirus; HPV-16, Human Papillomavirus 16; EBV, Epstein-Barr Virus; HTLV-1, Human T cell Leukemia/lymphoma Virus type 1; CHIKV, Chikungunya Virus; HCV, Hepatitis C Virus; NDV, Newcastle Disease Virus; Polio, Poliovirus; IAV, Influenza A Virus; CVB3, Coxsackievirus B3; FMDV, Foot and Mouth Disease Virus; HPIV3, Human Parainfluenza Virus 3; HBV, Hepatitis B Virus.
Figure 2
Figure 2
Impact of autophagy on tumor progression. In normal cells, autophagy restricts the tumorigenesis by limiting genome instability and strong inflammation. However, when the tumor is established, autophagy has been shown to promote tumor development, including the tumor progression, migration, and the formation of metastasis. Autophagy has also been associated to a better resistance to antitumor radio- or chemotherapies. In contrast to support tumor, autophagy favors the antitumor immune responses, promoting the immunogenic cell death and the presentation of tumor antigens to the adaptive immune cells. Protumor effects of autophagy are written in red and antitumor effects in green. Effect of autophagy (blue) is indicated at different steps of tumor development. ROS, Radical oxygen species; EMT, Epithelial-Mesenchymal Transition.
Figure 3
Figure 3
Relations between oncolytic viruses and autophagy in tumor. Oncolytic viruses induce an immunogenic cell death by inducing autophagy, which favors the cell death of tumor-infected cells and the release of immunogenic molecules (e.g., HMGB1, ATP, or HSPs proteins). More specifically, CARds replication induces autophagy by an inhibition of mTORC1, which enhances the induction of cell death and the release of immunogenic molecules. MeV induces mitophagy to eliminate mitochondria, resulting to a decrease of apoptosis and an increase of necrosis, a more immunogenic cell death. NDV infection increases ER stress, resulting to an induction of autophagic cell death and the secretion of immunogenic molecules. In addition, HSV-2 infection can also perturb the tumor microenvironment by favoring the expression of pro-inflammatory molecules (e.g., TNFα, IL-1β; and GM-CSF) and limiting the production of immunosuppressive molecules (e.g., IL-10 and TGFβ). CRads, Conditionally Replicating Adenoviruses; MeV, Measles Virus; NDV, Newcastle Disease Virus; HSV-2, Herpes Simplex Virus 2; ADCD, autophagy-dependent cell death.
Figure 4
Figure 4
Role of virus-induced autophagy in tumor cell survival. Viral infections can induce autophagy in tumor cells, leading to a protection of tumor cells from stress-induced or immune cells-induced cell death. In one hand, autophagy protects tumor infected cells from stress conditions (e.g., starvation or hypoxia) by limiting the accumulation of damaged organelles or by increasing the expression of genes involved in cell survival (e.g., via the phosphorylation of SATA3). In another hand, virus-induced autophagy limits the induction of apoptosis, protecting tumor cells from death receptor- or mitochondria-mediated cell death. Autophagy also takes part in the resistance of infected tumor cells from immune cell lysis by targeting and neutralizing granzyme B activity. HTLV-1, Human T cell Leukemia/lymphoma Virus type 1; HBV, Hepatitis B Virus; HCV, Hepatitis C Virus; NDV, Newcastle Disease Virus; PRF/GzmB, Perforin/Granzyme B.
Figure 5
Figure 5
Autophagy induced under viral infection can perturb antitumor immunity. Autophagy can interfere with innate and adaptive immunity and impact the antitumor immune responses. Viruses-induced autophagy perturbs type I IFN pathway by limiting NF-κB activation and STAT1/STAT2 phosphorylation. Several viruses (e.g., SARS, IAV, PIV, and MeV) can also modulate mitochondria activity via mitophagy and prevent inflammation by inhibiting the release of ROS or by preventing the formation of inflammasome. Viral infections or autophagy can also modulate the expression MHC-I by tumor cells or DC, limiting the action of antitumor cytotoxic T cells. MCMC, Murine Cytomegalovirus; IAV, Influenza A Virus; MeV, Measles Virus; SARS, SARS-Coronavirus; PIV, Parainfluenza Virus; BTV, Bluetongue virus; MHC-I, Major Histocompatibility Complex I; PRF/GzmB, Perforin/Granzyme B, DC, dendritic cells.
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