The autophagy protein ATG5 is essential for protecting the mouse central nervous system from lethal infection with Sindbis virus (SINV). Orvedahl et al. (2010) reported that Atg5 deletion resulted in the delayed clearance of viral proteins, while also leading to an increase in neuronal cell death and the cellular accumulation of the adaptor protein p62 [also known as sequestosome 1 (SQSTM1)]. The authors further found that p62 acts as a cargo receptor mediating the selective clearance of SINV capsid proteins, thereby promoting cell survival ( Figure 2 ). High-throughput, genome-wide, small interfering RNA (siRNA) screening subsequently identified the host ubiquitin ligase SMURF1 as an essential factor for the colocalization of p62 and SINV capsid proteins as well as virophagy. Following the silencing of SMURF1, p62 lost its ability to target SINV ( Figure 2 ) (Orvedahl et al., 2011). The Fanconi anemia complementation group C (FANCC) protein was also found to mediate virophagy by interacting with the SINV capsid and promoting host antiviral defenses ( Figure 2 ) (Sumpter et al., 2016). SMURF1 and FANCC also target HSV-1 for selective degradation, suggesting that these two proteins generally function as virophagy factors (Orvedahl et al., 2011; Sumpter et al., 2016). A complex cell type- and infection status-dependent link exists between HIV-1 and autophagy. (Sagnier et al., 2015) reported that the HIV-1 reverse transcription activator Tat, a protein essential for viral transcription and virion production, is recognized by the adaptor protein p62/SQSTM1 in a ubiquitin-independent manner in CD⁴⁺ T-cells, following which it is degraded via selective autophagy ( Figure 2 ). HIV-1 is a “master” at manipulating host cellular mechanisms, including autophagy, and facilitates its own replication and infection through disrupting or hijacking host cellular autophagic mechanisms. Influenza A virus (IAV) is an important zoonotic pathogen, causing significant morbidity in humans and representing an ever-present threat to humanity. IAV achieves efficient cross-species transmission through reassortment or directing host adaptation processes (Taubenberger and Kash, 2010). When IAV containing avian PB2 infects mammalian cells, viral ribonucleoprotein (vRNP) forms aggregates that localize to the microtubule-organizing center in infected cells (Liu et al., 2021). Correspondingly, the selective autophagy receptor p62/SQSTM1 targets newly synthesized vRNPs through PB2, a viral polymerase subunit, inducing higher autophagic flux and greater autolysosome accumulation, which limits viral infection (Liu et al., 2021). p62 can also mediate the degradation of avibirnavirus proteins. Infectious bursal disease virus (IBDV) capsid protein VP2 is responsible for virus assembly, maturation, and replication. (Li et al., 2020c) revealed that p62 recognizes ubiquitinated VP2 proteins and specifically recruits them to autophagosomes ( Figure 2 ). p62 lacking the UBA or LIR can no longer promote VP2 degradation, indicating that p62 promotes the selective autophagic degradation of VP2 in a ubiquitin-dependent manner (Li et al., 2020c). It has been suggested that the ER-resident protein SCOTIN may act as a cargo receptor for virophagy and recruits non-structural 5A (NS5A), a key factor in hepatitis C virus (HCV) replication, into autophagosomes for degradation ( Figure 2 ) (Kim et al., 2016). In animal cells, the antiviral restriction factors tripartite motif-containing proteins (TRIMs) comprise a large family of pattern recognition receptors (PRRs) containing a RING domain, a B box domain, and a coiled-coil domain at the N-terminus; additionally, most TRIMs contain a variable C-terminal domain that plays a role in substrate binding (Kawai and Akira, 2011). TRIMs not only regulate autophagy initiation and nucleation, but also act as cargo receptors to mediate the selective autophagy of viral capsid proteins. For example, in Langerhans cells (LCs), TRIM5α mediates the assembly of autophagy-activating complexes to turn on the virophagy machinery (Ribeiro et al., 2016). In addition, TRIM5α recruits the HIV-1 capsid into autophagosomes for HIV-1 degradation through directly interacting with the capsid and ATG8s ( Figure 2 ) (Mandell et al., 2014a; Mandell et al., 2014b) ( Table 1 ).

Several studies have provided clear evidence that autophagy can also serve as an antiviral defense in plants, directly targeting viruses or individual viral components for degradation. The cotton leaf curl Multan virus (CLCuMuV) βC1 protein is a key factor in virus-induced disease symptoms and virus accumulation in plants (Jia et al., 2016). Haxim et al. (2017) showed that ATG8 directly targets βC1 for degradation, thereby protecting plants against this geminivirus ( Figure 2 ). Interestingly, the V32A mutation in βC1 disrupts the interaction between ATG8 and βC1, preventing βC1 degradation through autophagy. In Nicotiana benthamiana, CLCuMuV carrying the βC1^V32A mutation induces severe symptoms and viral DNA accumulation (Haxim et al., 2017). Similarly, tomato leaf curl Yunnan virus (TLCYnV) nucleoprotein C1 undergoes autophagic degradation through directly interacting with ATG8h ( Figure 2 ). During virophagy, exportin1 (XPO1) participates in the transfer of C1 from the nucleus to the cytoplasm and mediates the binding of ATG8h to C1 (Li et al., 2020b). When the autophagy-related genes ATG8h, ATG5, and ATG7 are separately knocked out in plants, the degradation of C1 is inhibited, thus promoting TLCYnV infection (Li et al., 2020b) ( Table 1 ).

In plants, besides the direct targeting of the core autophagy protein ATG8 to the viral component, virophagy also requires cargo receptors as intermediaries. Hafren et al. (2017) reported that selective autophagy limits cauliflower mosaic virus (CaMV) infection during compatible interactions between CaMV and host plants. Autophagy-defective Arabidopsis mutants (atg5 and atg7) develop more severe symptoms after CaMV infection than their wild-type counterparts. The viral capsid protein P4 specifically accumulates in Atg5 and Atg7 mutant strains, whereas the levels of other viral proteins remain unchanged. Furthermore, selective autophagy mediated by the cargo receptor NBR1 inhibits the accumulation of CaMV P4 ( Figure 2 ) (Hafren et al., 2017). NBR1-dependent selective autophagy has also been reported to function as an antiviral mechanism targeting RNA viruses. NBR1 inhibits turnip mosaic virus (TuMV) accumulation by targeting the TuMV helper component protease HCpro, a suppressor of antiviral RNA silencing ( Figure 2 ) (Hafren et al., 2018). Nevertheless, TuMV appears to antagonize NBR1-dependent autophagy during infection through the activity of different viral proteins, thus limiting its antiviral ability (see below). ATG6/Beclin1 reportedly acts as a selective autophagic cargo receptor and interacts with RNA-dependent RNA polymerase (RdRp) by targeting its GDD motif, which results in the autophagic degradation of RdRp and the inhibition of TuMV infection ( Figure 2 ) (Li et al., 2018). Silencing ATG6/Beclin1 or ATG8 to block autophagy can promote RdRp accumulation and viral infection and vice versa. That the GDD motif is relatively conserved and is found in the RdRps of most plant and animal viruses suggests that ATG6/Beclin1 may be a general cargo receptor in virophagic processes (Li et al., 2018). Recently, Jiang et al. (2021) identified a novel cargo receptor, P3IP, which induces and mediates the autophagic degradation of the rice stripe virus (RSV)-encoded RNA silencing suppressor (RSS) P3 protein ( Figure 2 ). The calmodulin-like protein rgs-CaM may also be a selective autophagic receptor that regulates viral infection. For example, tomato rgs-CaM can interact with and stimulate the autophagic degradation of a variety of viral RNA RSSs, including HCpro from potyvirus as well as the 2b protein from cucumber mosaic virus (CMV) and tomato aspermy virus ( Figure 2 ) (Nakahara et al., 2012) ( Table 1 ).

In summary, selective autophagy mediated by cargo receptors has been shown to play a key role in host protection against viral infection. Meanwhile, this antiviral mechanism is well conserved in animal and plant cells. The identification of receptors or adaptors for selective autophagy will greatly advance the understanding of virophagy and better reveal the biological processes underlying the role of selective autophagy in host–virus interactions.

The TOR kinase complex functions upstream of autophagy, controlling autophagosome biogenesis by negatively regulating the activity of the ATG1/ULK1 complex ( Figure 1 ). Some animal and plant viruses can activate TOR kinase activity to inhibit virophagy ( Table 2 ). For example, CaMV, a plant virus, binds to and activates TOR kinase through the multifunctional protein P6, which, in turn, blocks cellular autophagy and promotes CaMV infection ( Figure 1 ) (Zvereva et al., 2016). Regarding animal viruses, Blanchet et al. (2010) reported that HIV-1 envelope activates the mTORC1 pathway in dendritic cells (DCs), leading to impaired autophagy and, consequently, the blocking of autophagosome-mediated degradation ( Figure 1 ). Autophagy is a powerful inhibitor of herpes simplex virus 1 (HSV-1) pathogenesis in neurons (Yordy et al., 2012). However, HSV-1 serine/threonine kinase Us3 can antagonize autophagy in non-neuronal cells by activating mTORC1 activity and increasing the phosphorylation level of ATG1/ULK1 ( Figure 1 ) (Rubio and Mohr, 2019). Us3 can also directly phosphorylate ATG6/Beclin1 and inhibit its activity, which further suppresses cellular autophagy ( Figure 1 ) (Rubio and Mohr, 2019). Indeed, ATG6/Beclin1 is a target of many animal viral proteins ( Table 2 ). The HSV-1-encoded neurotoxic protein ICP34.5 binds to ATG6/Beclin1 and inhibits its autophagic function ( Figure 1 ) (Orvedahl et al., 2007). The HSV-1 ICP34.5 mutant lacking the ATG6/Beclin1 binding domain cannot inhibit autophagy in neurons or cause fatal encephalitis in mice (Orvedahl et al., 2007). Human cytomegalovirus (HCM1) expresses TRS1, a functional homolog of ICP34.5, which can also block autophagosome biogenesis ( Figure 1 ) (Chaumorcel et al., 2012). The N-terminal domain of TRS1 contains the Beclin1 binding region, which is crucial for inhibiting Beclin1-mediated autophagy (Chaumorcel et al., 2012). Another HCMV protein, IRS1, has also been reported to block autophagy by interacting with Beclin1 ( Figure 1 ) (Mouna et al., 2016).

In yeast and mammalian cells, in addition to its anti-apoptotic role, B-cell lymphoma 2 (Bcl-2) also exerts anti-autophagic activity through its interaction with Beclin1 (Pattingre et al., 2005). Some animal viral proteins function in a manner similar to that of host cell Bcl-2, i.e., they attenuate autophagy by directly interacting with Beclin1 ( Table 2 ). For example, Kaposi’s sarcoma-associated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68) encode the Bcl-2 paralogs ORF16 and M11, respectively. These viral Bcl-2 (vBcl-2) proteins mimic their cellular counterparts (cBcl-2) and inhibit autophagosome formation ( Figure 1 ) (Pattingre et al., 2005). Furthermore, structural and biochemical analysis has shown that vBcl-2 has a significantly higher affinity for Beclin1 and inhibits autophagosome formation to a greater extent than cBcl-2 (Ku et al., 2008). Because of the lack of a regulatory loop that can undergo phosphorylation by c-Jun N-terminal kinase (JNK), vBcl-2 can remain bound to Beclin1, indicating that vBcl-2 has evolved into a highly effective autophagy inhibitor (Wei et al., 2008). Whether plant viruses can inhibit the activity of ATG6/Beclin1 through phosphorylation, direct interaction, or any other mechanisms, thereby blocking autophagosome biogenesis, is unknown. Moreover, no homolog of yeast and mammalian Bcl-2 has been identified in plants, and it is unclear whether a mechanism similar to the Bcl-2-mediated regulation of the autophagy pathway exists in plants. More studies investigating the regulation of host autophagy by plant viral proteins are needed to elucidate these possibilities.

The ATG12-ATG5-ATG16 and ATG8/LC3-PE ubiquitin-like conjugation systems are essential for autophagosome formation and may also be a driving force for vesicle membrane deformation or bending. Some animal and plant viral proteins bind to certain proteins of these two sets of ubiquitin-binding systems, thus interfering with autophagosome biogenesis ( Table 2 ). The FLICE-like inhibitor protein (vFLIP) of KSHV, herpesvirus saimiri (HVS), and molluscum contagiosum virus (MCV) can inhibit autophagy by preventing ATG3 from binding and processing LC3 ( Figure 1 ) (Lee et al., 2009). Foot-and-mouth disease virus (FMDV) mediates the degradation of the ATG5-ATG12 complex through viral 3C^pro ( Figure 1 ) (Fan et al., 2017). The siRNA-mediated knockdown of ATG5-ATG12 significantly increases the FMDV load and vice versa (Fan et al., 2017). Plant viruses also adopt similar strategies to inhibit virophagy. For example, the γb protein of barley stripe mosaic virus (BSMV) interferes with the interaction between ATG7 and ATG8 in a competitive manner and disrupts autophagy-mediated antiviral defenses ( Figure 1 ) (Yang et al., 2018). IAV targets ATG8/LC3, the core component of autophagy, through the multifunctional protein M2, thereby disrupting autophagy. Beale et al. (2014) found that the cytoplasmic tail of IAV M2 contains a highly conserved LIR that mediates a direct interaction between M2 and LC3 in virus-infected cells and thereby promoting the mislocalization of LC3 to the plasma membrane. Moreover, mutations in M2 abolish LC3 binding, interfere with virus budding, and reduce the stability of virus particles.

Interference with cargo receptor-dependent selective autophagy is a commonly used strategy by animal and plant viruses to counteract host antiviral responses ( Table 2 ). Some arboviruses, such as dengue virus (DENV) and Zika virus (ZIKV), use the ER as a source of membranes to establish replicative organelles and promote their assembly and final maturation along the secretory pathway (Welsch et al., 2009). Correspondingly, host cells have evolved reticulophagy to cope with this stress. For example, the ER-localized cargo receptor FAM134B can limit the replication of DENV and ZIKV (Khaminets et al., 2015). However, these virus-encoded NS3 proteases specifically block reticulophagy by cleaving FAM134B at a single site in its reticular homology domain (RHD) ( Figure 1 ) (Lennemann and Coyne, 2017). p62/SQSTM1 plays an important role in mediating virophagy. For instance, p62/SQSTM1 can directly interact with the coxsackievirus B3 (CVB3) capsid protein VP1 and recruit it for autophagic degradation, which reduces intracellular viral protein production (Shi et al., 2013). Interestingly, CVB3 viruses use viral protease 2A^pro to cleave p62/SQSTM1, disrupting its function in selective autophagy ( Figure 1 ) (Shi et al., 2013; Mohamud et al., 2019). In contrast, Epstein–Barr virus (EBV) targets p62/SQSTM1 via the deubiquitinase BPLF1, which inhibits selective autophagy and promotes EBV replication and transmission ( Figure 1 ) (Yla-Anttila et al., 2021). Plant viruses employ a similar strategy to inhibit selective autophagy. For example, NBR1 targets the viral capsid protein P4 and mediates its autophagic degradation, which inhibits CaMV infection (Hafren et al., 2017). However, the P6 protein of CaMV can disrupt the interaction between host NBR1 and P4 and protect the inclusion bodies of viral replication factories from autophagic degradation ( Figure 1 ) (Hafren et al., 2017). In addition, TuMV VPg and 6K2 can reportedly antagonize the antiviral ability of NBR1-dependent autophagy by blocking the degradation of HCpro by NBR1; however, the molecular mechanism underlying this inhibition of autophagy remains unclear ( Figure 1 ) (Hafren et al., 2018).

In addition to activating the TOR kinase complex, inhibiting autophagic core protein activity, and disrupting selective autophagy, animal viruses can also interfere with autophagosome maturation and block autophagosome–lysosome fusion, thus suppressing antiviral autophagic activity ( Figure 1 ). SARS-CoV-2 restricts autophagy-associated signaling and blocks autophagic flux. Cells infected with SARS-CoV-2 show an accumulation of key metabolites, the activation of autophagy inhibitors such as AKT and SKP2, and a reduction in the levels of several proteins responsible for processes spanning from autophagosome formation to autophagosome–lysosome fusion (Gassen et al., 2021). In a recent study, the effect of individual SARS-COV-2 proteins on autophagy was systematically analyzed, and the authors found that E, M, ORF3a, and ORF7a promoted autophagosome accumulation, while also reducing autophagic flux (Hayn et al., 2021; Koepke et al., 2021). Additionally, ORF3a and ORF7a were reported to block autophagy by respectively interfering with autophagosome–lysosome fusion and lysosomal acidification (Hayn et al., 2021; Koepke et al., 2021). Miao et al., (2021) conducted an in-depth analysis of the mechanism by which ORF3a prevents autophagosome–lysosome fusion. ORF3a strongly interacts with VPS39, a component of the tethering factor HOPS (homotypic fusion and protein sorting) complex. The binding of ORF3a to VPS39 disrupts the assembly of the HOPS complex, which is followed by the failure of STX17-SNAP29-VAMP8 SNARE complex assembly. As the SNARE complex mediates autophagosome–lysosome fusion, this effect of ORF3a leads to the inhibition of autophagosome–lysosome fusion and the complete blockage of autophagic flux (Miao et al., 2021; Yim and Mizushima, 2021). Qu et al. (2021) showed that ORF3a has another effect associated with host autophagy. The core autophagy protein ATG6/Beclin1 is known to regulate lipid kinase Vps34 (PI3KC3) and to interact with mammalian ATG14 or UVRAG to form two phosphatidylinositol 3-kinase complexes with significantly distinct functions. The PI3KC3-C1 (ATG6/Beclin1-Vps34-Atg14) complex positively regulates autophagosome formation while the PI3KC3-C2 complex (ATG6/Beclin1-Vps34-UVRAG) mediates autophagosome maturation by promoting autophagosome–lysosome fusion (Levine et al., 2015). ORF3a interacts with the autophagy regulator UVRAG to selectively inhibit PI3KC3-C2 and promote the formation of PI3KC3-C1, thus inducing incomplete autophagy (Qu et al., 2021). It is not clear whether SARS-CoV-2 protein is normally targeted for autophagic degradation. If so, blocking fusion will allow SARS-CoV-2 to avoid lysosomal degradation and prevent the degradation products from being used for antigen presentation to T cells. If not, the accumulation of membrane-related components caused by incomplete autophagy may exert a positive effect on SARS-CoV-2 replication. Interestingly, several other intractable viruses adopt similar strategies to avoid autophagosome–lysosome fusion. Human parainfluenza virus type 3 (HPIV3) phosphoprotein (P) binds to SNAP29 and inhibits its interaction with STX17, thus preventing autophagosome–lysosome fusion mediated by these two host SNARE proteins (Ding et al., 2014). IAV utilizes M2 to block fusion, resulting in autophagosome accumulation. M2 physically interacts with TBC1D5 through its cytoplasmic tail, thereby abrogating TBC1D5-Rab7 binding, which is critical for autophagosome–lysosome fusion (Martin-Sancho et al., 2021). Hepatitis B virus (HBV) is one of the most successful human pathogens. Liu et al. (2014) showed that the HBV X protein (HBx) significantly impairs lysosomal acidification and affects lysosomal maturation, thereby inhibiting autophagic degradation. However, HBx can also bind to and enhance the enzymatic activity of PI3KC3, an enzyme vital for initiating autophagy, which, in turn, promotes autophagosome formation in infected cells (Sir et al., 2010). Consequently, inducing incomplete autophagy may allow HBV to both avoid autophagic degradation and promote its own replication through making use of the components of the autophagy machinery.

There are no reports to date of plant viruses interfering with the mechanism of autophagy similar to that seen with animal viruses; however, given that plant viruses may promote replication through autophagy biogenesis, and because they must avoid degradation via the autophagy pathway, plant viruses may “kill two birds with one stone” by blocking the last link in the autophagic process, that is, the autophagosome maturation and fusion steps.

Utilizing host proteins to evade being degraded by autophagy is a versatile mechanism adopted by viruses. Galectin-8 can detect nucleosomes containing picornaviruses (PVs) and mark them for autophagic degradation; meanwhile, PVs such as poliovirus can evade this detection with the aid of the host protein HRAS-like suppressor 3 (PLA2G16), thus evading clearance by autophagy and ensuring the delivery of viral genomes into the cytoplasm ( Table 2 ) (Staring et al., 2017). Rice streak virus (RSV) can induce an unfolded protein response (UPR) in both rice and tobacco. In turn, RSV-induced UPR activates the host’s autophagy pathway, targeting the RSV-encoded motor protein NSvc4 for autophagic degradation and inhibiting RSV movement between cells. Correspondingly, RSV NSvc4 hijacks UPR-activated type I J-domain proteins in plants to evade autophagic degradation ( Table 2 ) (Li et al., 2021).

Besides directly disrupting host autophagy, some plant- or animal-derived viruses can also hijack host cell autophagy, which leads to weakened host antiviral defense responses ( Table 3 ). Recently, Hou et al. (2021) found that CCDC50 negatively regulates the type I interferon (IFN) signaling pathway that is activated by animal RNA viral sensor RIG-I-like receptors (RLRs). Interestingly, in human monocytes (THP-1) infected with RNA viruses such as Sendai virus (SeV), vesicular stomatitis virus (VSV), or encephalomyocarditis virus (EMCV), CCDC50 expression is significantly enhanced, and CCDC50 specifically recognizes polyubiquitinated RLRs, resulting in the delivery of activated RIG-I/MDA5 into autophagosomes for degradation ( Figure 2 ) (Hou et al., 2021). Histone deacetylase 6 (HDAC6), a component of viral RNA-induced stress granules, acts as an antiviral immune complex and plays an active role in the type I IFN responses (Zheng et al., 2020). Coxsackievirus A16 (CA16) triggers p62-mediated selective autophagic degradation of HDAC6, inhibits type I IFN responses, and promotes viral replication ( Figure 2 ) (Zheng et al., 2020). Some viral proteins act directly as cargo receptors and manipulate selective autophagy to inhibit host antiviral responses. For example, human parainfluenza virus type 3 (HPIV3) matrix protein (M) translocates to host mitochondria and induces mitophagy through interacting with Tu translation elongation factor, mitochondrial (TUFM) and the autophagy protein LC3 ( Figure 2 ) (Ding et al., 2017). M-mediated mitophagy leads to the inhibition of type I IFN responses. The IAV PB1-F2 protein functions in a similar manner to HPIV3 M, simultaneously interacting with TUFM and LC3B to induce complete mitochondrial autophagy, which promotes the degradation of mitochondrial antiviral signaling protein (MAVS) and suppresses the host’s innate immunity (Wang et al., 2021a). Muscolino et al. (2020) detailed a mechanism by which viruses hijack cellular autophagy to degrade host signaling proteins and thus evade immunity. The M45 protein of murine cytomegalovirus induces the degradation of nuclear factor κ-light-chain-enhancer of activated B-cells (NF-κB) essential modulator (NEMO) and receptor-nuclear protein kinase 1 (RIPK1) by first promoting their sequestration as insoluble protein aggregates and then recruiting the retromer component vacuolar protein sorting 26B (VPS26B) and the LC3-interacting adaptor protein TBC1D5 to promote the degradation of the aggregates through selective autophagy ( Figure 2 ) (Muscolino et al., 2020). Like M45, the HSV-1 ICP6 protein also induces the aggregation and degradation of RIPK1 (Muscolino et al., 2020).

siRNA-mediated post-transcriptional gene silencing (PTGS) is a well-characterized conserved antiviral defense mechanism in higher plants. Key components involved in the PTGS mechanism include ARGONAUTE1 (AGO1) and the host RNA-dependent RNA polymerase 6 (RDR6)/suppressor of gene silencing 3 (SGS3) complex (Ding, 2010). During interaction with their hosts, plant viruses target these proteins for autophagic clearance to counteract host-mediated RNA silencing. Derrien et al. (2012) found that polerovirus P0 triggers AGO1 degradation through the autophagy pathway ( Figure 2 ). Subsequently, Michaeli et al. (2019) showed that P0 and AGO1 are associated with the ER, leading to their loading into ER-associated vesicles and, subsequently, their vacuolar degradation in an ATG5- and ATG7-dependent manner. In addition, ATG8-interacting proteins 1 and 2 (ATI1 and ATI2) are recruited to the ER and interact with AGO1 to promote the ER-associated autophagic degradation of AGO1 (Michaeli et al., 2019). TuMV infection has been reported to reduce the level of SGS3, which is essential for the biosynthesis of virus-derived small interfering RNA (vsiRNA) (Cheng and Wang, 2017). TuMV-encoded viral genomic connexin (VPg) interacts with SGS3 and induces its degradation and that of its interacting partner RDR6 through both 20S ubiquitin-proteasome and autophagic pathways ( Figure 2 ) (Cheng and Wang, 2017). Li and co-workers reported that geminiviruses appear to indirectly utilize the plant endogenous RNA silencing suppressor calmodulin-like protein (CaM) to inhibit the siRNA mechanism by promoting the autophagic degradation of SGS3 ( Figure 2 ) (Li et al., 2014; Li et al., 2017). Recently, Tong et al. (2021) identified a novel 71-amino acid virus-induced small peptide (VISP1) in plants that acts as an autophagy cargo receptor. VISP1 overexpression induces selective autophagy, which attenuates SGS3/RDR6-dependent viral siRNA amplification and enhances viral infection; meanwhile, VISP1 mutants display the opposite effect. Some plant viruses can induce the upregulation of VISP1 expression, thus mediating selective autophagic degradation of SGS3/RDR6 and, consequently, promoting self-replication and infection ( Figure 2 ).

Remorins (REMs) are plant-specific membrane-associated proteins that play an important role in the interaction between plants and pathogens (Konrad et al., 2014). Fu et al. (2018) reported that S-acylation is a prerequisite for NbREM1 to target plasma membrane microdomains and is also required for its antiviral function, i.e., the inhibition of intercellular virus transport. Meanwhile, the RSV motor protein NSvc4 interacts with NbREM1 and interferes with its S-acylation; accumulated (untargeted) NbREM1 is degraded by autophagy, leading to the downregulation of NbREM1. In summary, RSV attenuates NbREM1-mediated antiviral activity, which promotes viral infection ( Figure 2 ) (Fu et al., 2018). Similarly, Cheng et al. (2020) reported that TuMV VPg interacts with REM1.2 and mediates its degradation through the 26S ubiquitin-proteasome and autophagy pathways ( Figure 2 ).

Viruses can also directly use the autophagy machinery to promote their own replication. For example, TuMV upregulates NBR1-mediated selective autophagy in a UPR-dependent manner and targets viral RdRp-containing virus replication complex (VRC) to the vacuolar membrane, which promotes viral replication and virion accumulation through cascades of protein–protein interactions ( Table 3 ) (Li et al., 2020a). Animal viruses also induce autophagosome accumulation by activating the UPR; however, they do not promote the degradation of autophagic proteins (Sir et al., 2008). Importantly, this autophagosome accumulation enhances HCV replication, suggesting that HCV uses an incomplete autophagic response to promote its replication (Sir et al., 2008). The production and envelopment of another animal virus, HBV, is also dependent on the host autophagy machinery. Unsurprisingly, HBV enhances the autophagy process in host cells without promoting protein degradation. This enhancement is mediated by HBV small surface protein (SHBs), which induces autophagy via triggering UPR and ER stress (Li et al., 2011).

In summary, plant and animal viruses employ several strategies to manipulate the autophagy machinery of their hosts. Viruses promote antiviral factor degradation by activating selective autophagy receptors or inducing the expression of negative immune regulators in their hosts. Additionally, virus-encoded proteins act as selective autophagy receptors and mediate autophagy, thus obstructing antiviral responses. Finally, some viruses use their host’s autophagic process directly, but do not promote autophagic protein degradation to enhance viral replication.