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  • br The complementary role of chaperone

    2023-01-09


    The complementary role of chaperone mediated autophagy Chaperone-mediated autophagy (CMA) mediates the degradation of specific cellular proteins and participates in the regulation of lipid metabolism, DNA repair, or the response to stress (Kaushik and Cuervo, 2018). CMA provides an alternative pathway to macroautophagy for cytosol surveillance and promotes MHC II presentation of cytoplasm-derived epitopes. Together, both pathways accounts for 10–30 % of the antigenic peptides presented by MHC II (Pérez et al., 2016). About 30% of soluble cytosolic proteins bear a “KFERQ” peptide motif recognized by the cytosolic chaperone HSPA8/HSC70 in association with HSP90, which targets them to late endosomes or lysosomes. This chaperone/cargo complex interacts with lysosome-associated membrane protein2A (LAMP2A), sustaining the translocation of CMA targets into the lysosomal lumen for processing and MHC II presentation (Cuervo and Dice, 1996; Zhou et al., 2005). Thus, CP2 is constituted of at least two alternative delivery routes (Fig. 1, violet arrows), the CPA-mediated and autophagosome-mediated pathways, mirroring the cytosolic and vacuolar pathways previously described for CP1 (Fig. 1, yellow arrows). CMA-mediated CP2 may be regulated by LAMP-2 isoforms expression, since LAMP-2A overexpression, but not of LAMP-2B nor LAMP-2C, increases the capacity of B cells to present cytosolic E64 receptor to CD4+ T cells. Conversely, expression of the LAMP2C isoform is strongly increased upon B cell activation by Toll like receptor (TLR) agonists and interferes with the CMA process (Pérez et al., 2016). Upon ectopic expression of LAMP2C, CMA-dependent MHC II-restricted presentation by B cells is inhibited, while proteins bearing a “KFERQ” signal accumulate in the cell cytosol (Pérez et al., 2016). LAMP-2C seems therefore to serve as a natural inhibitor of CMA that can selectively skew MHC II presentation of cytoplasmic antigens in response to external cues. Although the effect of CMA activity on immunity in vivo remains largely unknown, several lines of evidence point to the relevance of this pathway in the development of autoimmune diseases, such as systemic lupus erythematosus (SLE) (Wang and Muller, 2015). The accelerated lupus-like phenotype observed in MRL/lpr mouse model is attributed to a deficit in FAS-Receptor activity, notably in CD4+ T cells and B cells (Watson et al., 1992). In addition to these defects, it was shown that in MRL/lpr splenic B cells the CMA pathway is deregulated and LAMP2A and HSPA8 are overexpressed (Macri et al., 2015). Together with higher CMA activity, an increase in lysosomes size and a significant raise in endocytic pH were measured in MRL/lpr B cells. This suggests that alterations of lysosomes dynamics and CMA activity might lead to higher antigen presentation at the APC surface and consequently to an hyperactivation of autoreactive CD4+ T cells during SLE (Wang and Muller, 2015). Complementary to these observations, P140 (lupuzor®), a drug beneficial for the treatment of SLE patients (Schall et al., 2012), compromises CMA in B cells, by disrupting, at least in part, HSPA8/HSP90 heterocomplexes (Page et al., 2009). The consequence of CMA inhibition may be a reduction or a qualitative change in autoantigen processing and presentation by MHC II, causing a weaker priming of autoreactive T cells and an improvement of the autoimmune status in patients with SLE. These results confirm that pharmacologically harnessing all forms of autophagy-dependent antigen presentation might have interesting translational applications in treatment of immunological pathologies.
    Molecular mechanisms regulating autophagy-dependent antigen presentation The lack of necessary nutrients in cell or a whole organism triggers autophagy to degrade macromolecules and recycle amino acids and other biochemical components essential for continued cell and tissue survival (Kuma et al., 2004; Mizushima et al., 2003). Conserved signalling pathways control autophagy in response to environmental cues that may include microbial stimuli or cytokines, in particular in APCs. In addition to the aforementioned Atg and LC3 molecules, several other molecules have been involved in antigen presentation or immune cell activation.