Thyroid Hormone Receptor Antagonist (1-850) br Innate immune

Innate immune mechanisms that confront viral infection
Autophagy induction by virus sensing
Antiviral xenophagy and virophagy The presence of viral particles within autophagosomal structures has been visualized in only rare instances. This is the case for HSV-1 when it is devoided of ICP34.5, a virulence component able to oppose autophagic response by interfering with BECLIN-1 functions. In this setting, the autophagic activity that targets the virus relies on PKR engagement for its induction [54] but does not seem to substantially impact viral replication, at least in vitro[55]. Given that viruses can invade host cells through phagocytosis or clathrin-dependent internalization, the autophagic targeting of viral particles does represent a mean for early resistance to infection. Indeed, portions of the plasma membrane that include clathrin can participate in autophagosome formation and proteins of the autophagy machinery can be recruited to developing phagosomes [56], [57], suggesting that both phenomenon could be involved in anti-viral autophagy subsequently to virus entry. Apart from the possibility to target intact viral particles, autophagy can be activated to degrade particular component of viruses, a process referred to as virophagy [58], [59]. For example, the Thyroid Hormone Receptor Antagonist (1-850) of the Sindbis virus (SINV) can be selectively targeted to autophagosomes by the p62 receptor [6]. A search for factors involved in such a targeting identified numerous proteins that were not known to participate in autophagy processes [58]. Among them, the E3 ligase SMURF1 was identified as an important factor for the autophagic targeting of SINV capsid proteins as well as for the autophagic targeting of cytoplasmic HSV-1 virions Thus, a given factor is susceptible to contribute to the autophagic response directed to distinct types of viruses. By analyzing 44 autophagy-related factors for their capacity to bind viral proteins, an interactome study revealed that more than one third of them could effectively interact with virus components from five different RNA virus families [60]. Although the functional consequences of such interactions remain to be explored, this range indicates a high degree of interaction between RNA virus components and the autophagy machinery. The effective role of anti-viral autophagy/virophagy in the resistance to virus infection may well depend on the type of cells involved. While in cells with an active mitotic activity, virophagy seems to prominently activate anti-viral innate immunity, it may preferentially impact viral infection by viral factor degradation in neurons [61]. Proteins of the tripartite motif (TRIM) family are RING ubiquitin ligases that regulate multiple functions, including innate immune responses to viruses and autophagy. TRIM5α rapidly restricts infection by retroviruses prior to reverse transcription, in a species-specific manner. TRIM5α interaction with the HIV-1 viral capsid destabilizes the capsid lattice and amplifies the constitutive implication of TRIM5α in innate immune signaling via the UBC13/UEV1A–TAK1–AP1–NF-κB axis [62], [63], [64]. In addition, TRIM5α associates with activated autophagy initiation factors such as ULK1 and BECLIN 1. It also acts as an autophagy receptor that directly targets the HIV-1 capsid protein p24 for autophagic degradation by using a SPRY domain and LC3-interacting regions motifs [65]. This may contribute to retrovirus restriction by autophagic degradation, although the process might not be efficient in epithelial cells [66]. Among human DCs, HIV-1 restriction by TRIM5α was marked in Langerhans cells (LCs) but marginal in subepithelial DCs expressing the C-type lectin DC-SIGN. In LCs, HIV-1 restriction relies on the uptake of the virus by the C-type lectin Langerin, its internalization in Birbeck granules and a TRIM5α-dependent activation of the autophagy machinery (with a prominent role for ATG5 and ATG16L1) for degradation [67] (Fig. 2C). Human TRIM5α function thus as a cell-specific restriction factor of HIV-1 that activates autophagy subsequently to virus–Langerin surface interaction. Other TRIM factors are involved in induction of autophagy by viruses. Thus, the influenza A virus, the encephalomyocarditis virus (EMCV) and HSV-1 all involved several TRIMs for autophagy induction. While some TRIMs were preferentially recruited upon particular virus infections (e.g., TRIM56/HSV-1, TRIM25/Influenza A virus, TRIM 13/EMCV) and correlated with known contribution to innate immune mechanisms, others were common to all three infections (TRIM21, TRIM23, TRIM41) [68]. Among the latter, TRIM23 promoted p62-mediated selective autophagy due to autophosphorylation of its GTPase domain that triggered Tank binding kinase1 (TBK1) activation and p62 phosphorylation. TRIM23 was also involved in autophagy induction associated with RSV, adenovirus and SINV and participated in the constraint autophagy exerts on HSV-1, SINV and adenovirus [68]. The exact mechanisms involved in TRIM23 recruitment during virus infection, and in particular whether early events of infection contribute to it, remain to be investigated. TRIM proteins are thus capable of operating as both receptors for viral product and partners of the autophagy machinery activated during infection.