Autophagy and antiviral immunity
Introduction
Synthesis and degradation of intracellular proteins and organelles is required to maintain cellular homeostasis. The principal pathways responsible for the degradation of proteins in eukaryotes are the proteasome pathway and autophagy. The ubiquitin–proteasome system is involved in the constitutive degradation of soluble short-lived proteins that undergo continual turnover in living cells [1]. Autophagy, which was originally characterized as a starvation-induced response, delivers long-lived proteins and entire organelles for lysosomal degradation [2]. There are three types of autophagy: microautophagy, chaperon-mediated autophagy (CMA) and macroautophagy [3]. Microautophagy is characterized by the uptake of cytoplasmic components at the lysosome outer membrane via budding into the lysosome, through an undefined molecular mechanism. The CMA pathway is only conserved in higher eukaryotes and Ribonuclase A was identified as the first CMA substrate, which has a specific motif, KFERQ, necessary for degradation [4]. The chaperone protein Hsc70 recognizes this motif and interacts with lysosomal membrane protein (lamp) 2a, which is a peptide transporter [5, 6, 7]. Proteins are translocated into the lumen of lysosomes where they are subsequently degraded. Macroautophagy (hereafter as autophagy) is the major route of degradation of cytoplasmic constituents, which is mediated by the formation of the autophagosome, followed by its fusion with lysosomes. The autophagosome is a double membrane vesicle which forms via the elongation of a cup-shaped membrane and allows recycling of degraded proteins. A class of genes termed, autophagy-related genes (Atg), specifically regulate the process of autophagy. Yeast genetic studies have identified more than 20 Atg genes required for autophagy [8]. Two ubiquitin-like conjugation systems are necessary for autophagosome formation [9]. Once formed, the autophagosome fuses with the lysosome and, the cytoplasmic constituents are released into the lumen of the lysosomes and subsequently degraded by hydrolases, and are recycled through lysosomal transporters. The precise molecular mechanism of autophagy has been covered extensively by excellent reviews elsewhere [2, 10, 11].
In addition to the classical homeostatic function of autophagy described above, the importance of autophagy has now been defined in multiple biological processes including development, differentiation, and tissue remodeling [12]. Not surprisingly, autophagy is involved in both the prevention and pathogenesis of certain types of diseases [13]. Recent studies have shed light on how the immune system utilizes autophagy to fight microbial infection, while some pathogens have exploited this process for their own survival and replication [14, 15]. In this review, we focus on the role of autophagy in antiviral innate and adaptive immune responses.
Section snippets
The autophagosome as site of viral replication
Several viruses have been shown to subvert the autophagic machinery for their own replication and survival advantage. During poliovirus [16] and equine arteritis virus [17] infection (both positive stranded RNA viruses), the membranes that are induced resemble autophagosomes containing the characteristic double-membrane-bound morphology. The reduction of Atg12 and LC3 (two critical autophagy genes) by siRNA resulted not only in a reduction of extracellular poliovirus and Rhinovirus but also in
Autophagy limits viral replication and pathogen-induced cell death
Autophagy plays an integral pro-survival role during starvation, stress and infection. Several studies indicate that viral replication and infection-induced cell death could be limited by autophagy. In plants, autophagy exerts antiviral effects against tobacco mosaic virus (TMV) by (i) restricting cell death to the infection site, and (ii) limiting replication and cell-to-cell movement of TMV [24••]. In mammalian hosts, encephalitis induced by Sindbis virus can be reduced by the forced
Concluding remarks
Recent studies have demonstrated that autophagy is a fundamental process for anti-viral defense. It is becoming clear that autophagy plays a key role in innate recognition of viruses, innate effector function of viral destruction, and in the presentation of cytosolic viral antigens to CD4 T cells. Not surprisingly, viruses have developed strategies to use or subvert autophagy for their own benefit, and to prevent xenophagy by encoding inhibitors of this pathway. While evidence for autophagy as
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Dr Joseph M. Thompson for critical reading of the manuscript. This study was supported by grants from the National Institute of Allergy and Immunology (AI054359, AI062428, AI064705). H.K.L. was supported by the Ministry of Science and Technology of Korea and is a recipient of an Anna Fuller fellowship. A.I. is a recipient of the Burroughs Wellcome Investigators in Pathogenesis of Infectious Disease.
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