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TLRs and autophagy in innate immunity. (A) Cell wall components of Gram-positive bacteria and yeast are recognized by TLR2 whose activation triggers the association of LC3 with the phagosomal membrane and promotes phagolysosomal fusion. Phagocytosis of dead cells through recognition of surface PtdSr by Tim4 also utilizes LAP. LAP is also critical for processing and presentation of HSV antigens for MHC II by DCs. (B) Several TLRs are known to induce autophagy. (C) In pDCs, autophagy enables TLR7 recognition of cytosolic virus replication products or cytosolic viral genomes, resulting in both type I interferons and proinflammatory cytokine production (orange lines). In addition, TLR9 signaling for type I interferon production requires Atg5, possibly through the LAP-dependent signaling pathway (dotted green lines). Cytokine induction downstream of TLR9 occurs independently of Atg5 (solid line).
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Autophagy is an evolutionarily ancient process eukaryotic cells utilize to remove and recycle intracellular material in order to maintain cellular homeostasis. In metazoans, the autophagy machinery not only functions in this capacity but also has evolved to perform a diverse repertoire of intracellular transport and regulatory functions. In respons...
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... paramyxovirus Simian virus 5 (SV5) in pDCs depends on autophagy. Curiously, SV5 infection of pDCs did not result in IL-6 secretion, and replication of SV5 was not a prerequisite for TLR7 stimulation. As discussed below, these data are consistent with the role of autophagy in promoting TLR7 and TLR9 signaling for type I interferon production (30) (Fig. 3). These data indicate that autophagy is needed for viral recognition through endosomal TLRs for certain ssRNA ...
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... of the autophagy machinery have also been linked to phagosome maturation, resulting in TLR-dependent pathogen destruction (71). This seminal work demonstrated that macrophages utilize Atg proteins to recruit LC3 to the phagosomal membrane for efficient fusion with lysosomes (Fig. 3). Zymosan-treated RAW264.7 cells showed rapid recruitment of LC3 to zymosan-containing phagosomes and induced phagosome fusion with lysosomes. This was inhibited by genetic deletion of TLR (Tlr2 -/-) or Atg5/Atg7. Intriguingly, no double-membrane structures were observed proximal to LC3 + phagosomes in zymosan-treated cells, sug- ...
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... endosomes facilitates TLR9-dependent type I interferon synthesis independently of canonical autophagy. Collectively, LAP plays a key role in phagosome maturation and degradation of internalized cargo, and possibly in phagosomal processing of microbial antigens for MHC II, and in endosomal TLR9 signaling for type I interferon production (Fig. ...
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... induction was first reported by Xu et al. (79), who demonstrated that TLR4 signaling induces autophagy in a TRIF-dependent, MyD88-independent manner in RAW264.7 cells. Further mechanistic insight was provided by Delgado et al. (80), who reported that TLR7 activation can also induce autophagy via a MyD88-dependent mechanism in RAW264.7 cells (Fig. 3). Shi and Kehrl (81) demonstrated that LPS stimulation of TLR4 indeed induces autophagy in macrophage cell lines, but observed a MyD88-dependent mechanism, whereas TLR1 and TLR3 stimulation induced autophagy through MyD88-and TRIF-dependent mecha- nisms, respectively. This report further demonstrated that MyD88 and TRIF engagement ...
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... The earliest study of cell autophagy is in yeast, more than 30 genes involved in the process of autophagy are found for the present, and the encoded products participate in various forming procedures of the autophagic bodies, including the induction of autophagy, nucleation, expansion, mature, and fusion of vacuole, ect (Glick et al., 2010). Klionsky named these autophagy-related genes as ATG in 2003 (Yordy et al., 2013), representing the autophagy related genes and the corresponding proteins (Yu and Melia 2017). ...
Autophagy is a major degradation process of cytoplasmic components in eukaryotes, and executes bulk and selective degradation of targeted cargos. A set of autophagy-related (ATG) proteins participate in various stages of the autophagic process. Among ATGs, ubiquitin-like protein ATG8 plays a central role in autophagy. The expression of ATG8 affects many intracellular progresses. Here we report that the amino acid sequence of AtATG8 and TaATG8 protein share a high similarity of 84.03%, we found that TaATG8 involved in the abiotic stresses, such as drought, salt stress and nutrient deficiency. Our results indicated that TaATG8 gene participates in resisting against abiotic stresses in the stage of seed germination, seedling and adult. Moreover, TaATG8 plays an important role in the process of Arabidopsis defending against biotic stress caused by the infection of powdery mildew through HR. Hydrogen peroxide acts as an important metabolic product and signaling molecule in the process of TaATG8 resisting to powdery mildew.
... Leishmania RNA virus (LRV) induces type I IFN production by activating TLR3 and TRIF, which triggers the ATG5-mediated autophagyinduced degradation of NLRP3 inflammasome in macrophages [224]. ATG5 also facilitates the production of TLR9-induced IFN-I in pDCs infected with HSV-1 [225]. STING1 is essential for an RNA-virus triggered autophagy, foot-and-mouth disease virus (FMDV)induced integrated stress response originates from RIG-I, which transmits signals to STING1 and leads to degradation of STING1 itself [226]. ...
Autophagy is an evolutionarily conserved catabolic cellular process that exerts antiviral functions during a viral invasion. However, co-evolution and co-adaptation between viruses and autophagy have armed viruses with multiple strategies to subvert the autophagic machinery and counteract cellular antiviral responses. Specifically, the host cell quickly initiates the autophagy to degrade virus particles or virus components upon a viral infection, while cooperating with anti-viral interferon response to inhibit the virus replication. Degraded virus-derived antigens can be presented to T lymphocytes to orchestrate the adaptive immune response. Nevertheless, some viruses have evolved the ability to inhibit autophagy in order to evade degradation and immune responses. Others induce autophagy, but then hijack autophagosomes as a replication site, or hijack the secretion autophagy pathway to promote maturation and egress of virus particles, thereby increasing replication and transmission efficiency. Interestingly, different viruses have unique strategies to counteract different types of selective autophagy, such as exploiting autophagy to regulate organelle degradation, metabolic processes, and immune responses. In short, this review focuses on the interaction between autophagy and viruses, explaining how autophagy serves multiple roles in viral infection, with either proviral or antiviral functions.
... Based on the way that intracellular substances are transported to lysosomes, autophagy can be divided into macroautophagy, microautophagy, and molecular-chaperone-mediated autophagy [12]. The term "autophagy" is frequently used to refer to macroautophagy, since this is the most frequently observed autophagy process and has been the subject of a large amount of research [13,14]. ...
MicroRNAs (miRNAs) are endogenous small and noncoding RNA molecules (18–25 nt) that can regulate expression of their target genes post-transcriptionally. Previously, using high-throughput sequencing data obtained on a Solexa platform, we found that Bos taurus bta-miR-2904 (miR-2904) was significantly upregulated in Madin–Darby bovine kidney (MDBK) cells infected with bovine viral diarrhea virus (BVDV) strain NADL at 2, 6, and 18 h postinfection (hpi) compared to uninfected MDBK cells. Moreover, miR-2904 overexpression significantly reduced BVDV replication. However, the mechanism by which miR-2904 inhibits viral replication remains unclear. In this study, we used electron microscopy, laser confocal microscopy, dual-luciferase reporter analysis, real-time PCR, and Western blot assays to investigate the effect of the miR-2904 expression on BVDV NADL replication and virus-infection-induced autophagy. The results indicate that miR-2904 inhibits autophagy of MDBK cells by targeting autophagy-related gene 13 (ATG13), and overexpression of miR-2904 inhibited the replication of BVDV NADL.
... By altering or evading autophagy, intracellular invaders can cause host cell death. The pathophysiological manifestations depend on the comprehensive regulation between autophagy and antimicrobial immunity (Yordy et al., 2013). ...
Autophagy is a catabolic process, which can degrade worn-out organelles and invading pathogens. The activation of autophagy regulates innate and adaptive immunity, playing a key role in response to microbial invasion. Microbial infection may cause different consequences such as the elimination of invaders through autophagy or xenophagy, host cell death and symbiotic relationship. Pathogens adapt to autophagy mechanism and further relieve intracellular stress, which is conducive to host cell survival and microbial growth. The regulation of autophagy forms a complex network through which host immunity is modulated, resulting in a variety of pathophysiological manifestations. The modification of autophagic pathway is an essential target for the development of antimicrobial drugs.
... Although studies have shown that autophagy plays distinct roles in host-virus interaction, corresponding to different viruses and host cell types, autophagy can be used to degrade viral components, viral particles, and even host factors required for viral replication; autophagy is therefore an important innate antiviral response (Choi et al., 2018;Ismayil et al., 2020;Yang et al., 2020). Many studies have confirmed that autophagy plays an antiviral defense role in host-virus interaction through silencing or mutating ATGs (Liu et al., 2005;Yordy et al., 2013). ...
Viruses typically hijack the cellular machinery of their hosts for successful infection and replication, while the hosts protect themselves against viral invasion through a variety of defense responses, including autophagy, an evolutionarily ancient catabolic pathway conserved from plants to animals. Double-membrane vesicles called autophagosomes transport trapped viral cargo to lysosomes or vacuoles for degradation. However, during an ongoing evolutionary arms race, viruses have acquired a strong ability to disrupt or even exploit the autophagy machinery of their hosts for successful invasion. In this review, we analyze the universal role of autophagy in antiviral defenses in animals and plants and summarize how viruses evade host immune responses by disrupting and manipulating host autophagy. The review provides novel insights into the role of autophagy in virus–host interactions and offers potential targets for the prevention and control of viral infection in both plants and animals.
... Harmful substances, misfolded proteins, and damaged organelles are separated and wrapped into the autophagosomes, which are transported into lysosomes and degrade the cargoes [1][2][3][4]. This process is essential for maintaining cell physiological homeostasis, including cell growth, development, repair, and survival, as well as responding to starvation or other environmental stresses [5]. Disorders in autophagy regulation are related to many human diseases, such as neurodegenerative diseases, metabolic disorders, and cancer [6][7][8]. ...
Nuclear autophagy is an important selective autophagy process. The selective autophagy of sexual development micronuclei (MICs) and the programmed nuclear degradation of parental macronucleus (paMAC) occur during sexual reproduction in Tetrahymena thermophila. The molecular regulatory mechanism of nuclear selective autophagy is unclear. In this study, the autophagy-related protein Atg5 was identified from T. thermophila. Atg5 was localized in the cytoplasm in the early sexual-development stage and was localized in the paMAC in the late sexual-development stage. During this stage, the degradation of meiotic products of MIC was delayed in atg5i mutants. Furthermore, paMAC was abnormally enlarged and delayed or failed to degrade. The expression level and lipidation of Atg8.2 significantly decreased in the mutants. All these results indicated that Atg5 was involved in the regulation of the selective autophagy of paMAC by regulating Atg8.2 in Tetrahymena.
... In brief, ATG14 is a key subunit in determining the role of the PI3K complex during autophagy, while VPS38 is essential to mobilize the vesicles along the endocytic route [15,18,19]. However, recent studies have demonstrated that not only the ATGs are involved in the regulation of other cellular functions, such as programmed cell death, aging, immune system, viral replication, tumorigenesis and others [20][21][22][23][24][25][26][27][28][29][30][31][32][33], but also that VPS38/ UVRAG plays alternative functions that became more evident in the past few years. For example, VPS38/UVRAG participates in the regulation of the translocation of autophagy related gene 9 (ATG9) (a lipid scramblase that mediates autophagosomal membrane expansion [34]), to the autophagosome and its association with important effectors of retrograde vesicular transport [35,36]. ...
In insects the reserve proteins are stored in the oocytes into endocytic-originated vesicles named yolk organelles. VPS38/UVRAG and ATG14 are the variant regulatory subunits of two class-III ATG6/Beclin1 PI3K complexes that regulate the recruitment of the endocytic (complex II) and autophagic (complex I) machineries. In a previous work from our group, we found that the silencing of ATG6/Beclin1 resulted in the formation of yolk-deficient oocytes due to defects in the endocytosis of the yolk proteins. Because ATG6/Beclin1 is present in the two above-described PI3K complexes, we could not identify the contributions of each complex to the yolk defective phenotypes. To address this, here we investigated the role of the variant subunits VPS38/UVRAG (complex II, endocytosis) and ATG14 (complex I, autophagy) in the biogenesis of the yolk organelles in the insect vector of Chagas Disease Rhodnius prolixus . Interestingly, the silencing of both genes phenocopied the silencing of ATG6/Beclin1, generating 1) accumulation of yolk proteins in the hemolymph; 2) white, smaller, and yolk-deficient oocytes; 3) abnormal yolk organelles in the oocyte cortex; and 4) unviable F1 embryos. However, we found that the similar phenotypes were the result of a specific cross-silencing effect among the PI3K subunits where the silencing of VPS38/UVRAG and ATG6/Beclin1 resulted in the specific silencing of each other, whereas the silencing of ATG14 triggered the silencing of all three PI3K components. Because the silencing of VPS38/UVRAG and ATG6/Beclin1 reproduced the yolk-deficiency phenotypes without the cross silencing of ATG14, we concluded that the VPS38/UVRAG PI3K complex II was the major contributor to the previously observed phenotypes in silenced insects.
Altogether, we found that class-III ATG6/Beclin1 PI3K complex II (VPS38/UVRAG) is essential for the yolk endocytosis and that the subunits of both complexes are under an unknown transcriptional regulatory system.
... Autophagy-related genes (ATGs) also play important roles in regulating antiviral immune responses, both positively and negatively. They perform as adaptable intracellular transport systems [98]. ...
... In murine norovirus (MNV) infection, a series of ATG proteins including ATG5, ATG7, ATG12 and ATG16L1 are involved to disrupt viral replication complexes via an IFN-γdependent mechanism [98]. However, it had been shown that MHV replication does not require the autophagy gene ATG5 in vitro [96]. ...
The COVID-19 pandemic is caused by the 2019–nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus.
... With the further investigation into the relationship between ATG proteins inducing autophagy and type I IFN against viral infection, a high proportion of ATG proteins (about 36%) has a positive or negative function on promoting virus replication apart from the classical roles of ATG proteins in autophagy . Autophagy-related proteins, such as ATG4b, ATG5, ATG7, ATG9a and ATG12 also play important roles in the generation of both innate and adaptive immune responses against viral infection (Chen et al., 2014;Fan et al., 2017;Jounai et al., 2007;Lee et al., 2007;Saitoh et al., 2009;Yordy et al., 2013). Among a number of ATG proteins, the subunit ATG13 serves as an adaptor which regulates the process of autophagy (Wallot-Hieke et al., 2018). ...
... An innate immune response is mediated by PRRs, including Toll-like receptors (TLRs), specifically recognizing pathogen-associated molecular patterns (PAMPs), resulting in induction of an antiviral interferon response. TLR7-as well as TLR9-induced interferon production in response to infection by Vesicular stomatitis Indiana virus (VSV) and herpes simplex virus type 1 (HSV-1) respectively, relies on the key autophagy protein Atg5 155,156 . Moreover, TLR adapter proteins MYD88 and TRIF bind to Beclin1 to disrupt its inhibition by B cell lymphoma-2 (BCL-2) and ultimately induce autophagy (Figure 7). ...
Phleboviruses, in the Phenuiviridae family within the Bunyavirales order, are important pathogenic arthropod-borne viruses (arboviruses), causing severe diseases in humans and domestic animals. Outbreaks are no longer limited to tropical and developing countries. Global trade, deforestation and global warming are reasons for the expansion of arthropod vectors, and the viruses they carry. The mosquito-borne phlebovirus Rift Valley fever (RVFV) spread from sub-Saharan parts of Africa over the entire continent and to the Arabic peninsula during the last two decades. As it already happened for other arboviruses (e.g. dengue virus), RVFV is now at risk of introduction into Southern Europe. Phleboviruses represent a risk to public health and agricultural productivity and must be taken seriously as potential emerging and reemerging pathogens. For humans, neither specific antiviral treatments nor vaccines are currently approved. Ideally, treating phlebovirus infection in humans, would target early virus-host cell interactions, preventing the release of the virus genome into the cytosol. Yet, the details of the entry pathways exploited by phleboviruses are mostly elusive, awaiting to be uncovered. For my PhD project, I used Uukuniemi virus (UUKV). UUKV is a validated biosafety level (BSL)-2 model for phleboviruses of higher biosafety classification such as RVFV. Our lab previously reported that UUKV enters human host cells by receptor-mediated endocytosis, transits Rab5-positive early endosomes and penetrates the cytosol from late endosomal compartments with a pH value around 5.4. With the aim to identify additional host factors involved in UUKV entry, two genome-wide siRNA screens were performed. In those screens, VAMP3 was identified to facilitate late endosomal penetration of UUKV. The v-SNARE protein VAMP3 plays an important role in recycling endosome trafficking and the initiation of autophagy. In addition to VAMP3, several other autophagy-associated host factors were found as potential host factors in the siRNA screens for UUKV entry. The overall goal of my PhD project was to clarify the role of autophagy in phlebovirus entry and decipher the molecular mechanisms subverted by phleboviruses to penetrate human host cells. Therefore, I analyzed UUKV infection by flow cytometry and confocal microscopy approaches. Within my PhD project, I assessed numerous autophagy-associated proteins for their role in UUKV infection. I identified the autophagic factor Atg7 and the small GTPase Rab11a as important host factors for UUKV infection. Atg7 is known mainly for its function in autophagosome maturation. Rab11a regulates recycling endosome trafficking and is involved in the initiation of autophagy. Addressing single steps of the virus entry process, I found that Atg7 and Rab11 specifically promote UUKV intracellular trafficking, while no effects were observed on other steps during early virus host cell interactions, i.e. binding or replication. Interestingly however, my results also indicate that Atg7 and Rab11 participate in UUKV infection in an autophagy-independent manner. In conclusion, this thesis expands our knowledge about entry of UUKV particles into human cells with a role of two more host factors, Rab11a and Atg7. Both proteins facilitate the transport of endocytosed viral particles from the plasma membrane to acidic endosomal compartments. Reaching these compartments is a critical step for acid-activated fusion and the subsequent release of the viral genome into the cytosol. Additionally, this work provides an indication of autophagy-independent functions of Atg7 in endosomal trafficking. The importance of Rab11a and VAMP3 in UUKV infection points towards a potential involvement of recycling endosomes in UUKV intracellular trafficking. UUKV represents a tool of choice to better understand the role of recycling endosomes in late endosomal trafficking, a function that remains elusive and is potentially exploited by other related and unrelated viruses.
