Autophagy, EVs, and Infections: A Perfect Question for a Perfect Time

Abstract

Autophagy, a highly conserved process, serves to maintain cellular homeostasis in response to an extensive variety of internal and external stimuli. The classic, or canonical, pathway of autophagy involves the coordinated degradation and recycling of intracellular components and pathogenic material. Proper regulation of autophagy is critical to maintain cellular health, as alterations in the autophagy pathway have been linked to the progression of a variety of physiological and pathological conditions in humans, namely in aging and in viral infection. In addition to its canonical role as a degradative pathway, a more unconventional and non-degradative role for autophagy has emerged as an area of increasing interest. This process, known as secretory autophagy, is gaining widespread attention as many viruses are believed to use this pathway as a means to release and spread viral particles. Moreover, secretory autophagy has been found to intersect with other intracellular pathways, such as the biogenesis and secretion of extracellular vesicles (EVs). Here, we provide a review of the current landscape surrounding both degradative autophagy and secretory autophagy in relation to both aging and viral infection. We discuss their key features, while describing their interplay with numerous different viruses (i.e. hepatitis B and C viruses, Epstein-Barr virus, SV40, herpesviruses, HIV, chikungunya virus, dengue virus, Zika virus, Ebola virus, HTLV, Rift Valley fever virus, poliovirus, and influenza A virus), and compare secretory autophagy to other pathways of extracellular vesicle release. Lastly, we highlight the need for, and emphasize the importance of, more thorough methods to study the underlying mechanisms of these pathways to better advance our understanding of disease progression.

Keywords: autophagy; exosome; extracellular vesicle; infectious disease; secretory autophagy; virus.

Figure 1

Interaction Between Vesicular Release Pathways, Autophagy, and Viral Infection. Several vesicle release pathways are utilized to maintain cellular homeostasis including the exosomal release pathway and secretory autophagy. Both pathways are capable of secreting viral products, although exosomes primarily secret non-infectious viral products with the exception of hepatitis C virus (HCV). Secretory autophagy has been shown to be responsible for the secretion of infectious particles in several cases. Degradative pathways include breakdown of select materials by fusion of autophagosomes, amphisomes, multivesicular bodies (MVBs), or endosomes with lysosomes. Up- or down-regulation of one of these pathways could potentially have feedback into other vesicular release or degradative systems to maintain cellular equilibrium. Degradative autophagy plays pro-viral and anti-viral roles during infection at various stages of autophagy. Red lines indicate a decrease/inhibition of autophagy by listed viral proteins, whereas blue arrows indicate a virally-induced increase or upregulation of autophagy. Viral proteins and viruses in purple boxes are targeted for degradation by the indicated portion of the autophagy pathway. For more detailed information, please see the main text. HIV-1, human immunodeficiency virus 1; CHIKV, chikungunya virus; HBV, hepatitis B virus; EBV, Epstein-Barr virus; SV40, simian virus 40; PV, poliovirus; IAV, influenza A virus; DENV, dengue virus; ZIKV, Zika virus; HTLV-1, human T-cell leukemia virus 1; HSV-1, herpes simplex virus type-1; KSHV, Kaposi's sarcoma-associated herpesvirus; MHV-68, murine gammaherpersirus 68.