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    • Inactivation of autophagy can also impact the surface intern

    2022-11-15

    Inactivation of autophagy can also impact the surface internalization of MHC I molecules, leading to increased antigen presentation. Inactivation of autophagy factors Atg5 and Atg7 in DCs causes elevation of MHC I surface levels by decreasing endocytosis due to a poor recruitment of adaptor-associated kinase 1 (AAK1) via LC3B (Loi et al., 2016). Reduced MHC I internalization in DCs enhances CD8+ T cell responses both in vitro and in vivo. In particular, Atg5 depletion favours the generation of influenza- and LCMV-specific CD8+ T cell, and a better overall immune control of the infection in vivo. Thus, the autophagy machinery seems to favour MHC II-restricted antigen presentation, while controlling MHC class I expression (Loi et al., 2016). Autophagy also provides an alternative pathway to proteasome-dependent processing in standard MHC I presentation (Tey and Khanna, 2012). In this case, TMC647055 Choline salt synthesis normally targeted to autophagy and displayed by MHC II through CP2 can also be loaded to MHC I in recycling endosomes (RE). This alternative MHC I presentation pathway is particularly useful upon herpesviruses infection, during which the ER-peptide loading and MHC I presentation are strongly inhibited by viral effectors (Verweij et al., 2015). During evolution however, Herpes simplex virus 1 has also acquired an autophagy inhibitor, that can interfere with alternative MHC I-restricted antigen presentation and favours viral escape (Budida et al., 2017). Autophagy also plays a role in CP1, although its contribution varies greatly between studies (Das et al., 2015). XCR1+ DCs exhibit enhanced autophagy as compared to other DC subsets, indicating that autophagy is highly active in these specialized cross-presenting cells (Mintern et al., 2015). Autophagy is involved in CP1 of chlamydial antigens (Fiegl et al., 2013), as well of soluble antigens in Epstein-Barr virus-transformed B cells in a TAP-independent manner (Dasari et al., 2016). The reasons for the existence of multiple CP1 pathways and the involvement of autophagy in some of them are currently unknown. It is however likely that the type of antigens, the APC subsets, and the immediate physiological environment have all a strong impact on the choice of the CP1 pathway and the involvement of autophagy in the process. DCs deficient in different Atg molecules have been shown to be unable to cross-present on MHC I yellow fever virus antigens derived from infected cells (Ravindran et al., 2014). However, this finding must be confirmed, since deletion of autophagy-related genes (Atg5, Atg7, Vps34) produce very contrasting effect of CP1. Results range from no effect at all, to inhibition of CP1 of soluble antigens but not of bacteria- or cell-associated antigens, to its opposite (Lee et al., 2010; Mintern et al., 2015; Parekh et al., 2017). Again, the role of LAP vs. bona fide autophagy on these observations is also difficult to establish and could further confuse the results of these analysis. However, Vps34-deficient XCR1+DCs display altered CP1 without exhibiting any major defects in endocytosis or phagocytosis (Parekh et al., 2017), suggesting that altered autophagy can be a likely cause for the observed phenotype.
    Targeting to and degradation of defective ribosomal products by autophagy One of the most important sources of endogenously produced antigens are defective ribosomal products (DRiPs). DRiPs are highly unstable proteins that are ubiquitinated and targeted for proteasome-mediated degradation shortly after their synthesis (Schubert et al., 2000). DRiPs result from different translation events linked either to nonsense-mediated decay, misincorporation of amino acids, premature translation termination, or abnormal post-translational modifications. DRiPs therefore represent a major source of endogenous or viral antigens leading to a faster MHC I presentation and recognition by CTLs (Schliehe et al., 2012; Schubert et al., 2000; Yin, 2003), independently of the half-life and proteolytic sensitivity of properly folded proteins (Anton and Yewdell, 2014). In addition to proteasome-mediated degradation, DRiPs are also degraded by autophagy and thus contribute to the generation of MHC II-restricted intracellular antigens (Lelouard et al., 2004; Wenger et al., 2012). Moreover, in stressful situations, DRiPs form the content of defective ribosomal products-containing autophagosome-rich blebs (DRibbles), which fuse their outer membrane with the plasma membrane and can release antigenic cargo in the extracellular milieu. DRibbles are thus considered a circulating antigen source that can be taken-up at a remote location by other DCs and cross-presented to initiate T cells responses (Fadul et al., 2011). Equivalent artificial autophagosomes have been used for the delivery of tumour antigens conjugated to nanoparticles, and shown to induce efficient CP1 and antitumoral responses in mouse models (Li et al., 2011).