CD46
CD46 is a cell surface transmembrane protein originally described as an inhibitor of complement activation(Liszewski, Post, & Atkinson, 1991). CD46 binds C3b and acts as a co-factor for factor I, a serum complement factor that cleaves deposited C3b into inactive C3b (iC3b), therefore preventing further activation of the complement cascade. Because of this cofactor activity, CD46 was originally named membrane cofactor protein (MCP). CD46 has several splice variants, with two potential cytosolic tails (Purcell et al., 1991), Cyt-1 and Cyt-2, that are capable of transducing signals across the cell membrane upon ligand binding. CD46 plays an important role as a potent co-stimulator of human CD4+ T-cell activation, leading to gene expression and metabolic changes (King et al., 2016; Kolev et al., 2015), that result in induction of an anti-inflammatory, IL-10-secreting regulatory T-cell phenotype (Kemper et al., 2003). Perhaps for this reason, CD46 is a ‘pathogen magnet’ (Cattaneo, 2004), being the cell surface receptor for human pathogens such as adenovirus B and D, measles virus, herpes virus 6, Neisseria and some strains of group A streptococcus (GAS).
Intracellular GAS survival can be limited by xenophagy (Nakagawa et al., 2004), and Joubet et al therefore tested whether this can be triggered by its binding to CD46 (Joubert et al., 2009). They found that antibody-mediated cross-linking of cell-surface CD46 led to de novo formation of autophagosomes in HeLa cells, which was found to be dependent on the interaction of Golgi-associated PDZ and coiled-coil motif containing protein (GOPC) with the CD46 Cyt-1, but not Cyt-2 tail. GOPC itself has been shown to interact with Beclin 1 (Yue et al., 2002), a protein central to nucleation of the autophagosome phagophore. Further, GOPC can interact with both CD46 Cyt-1 and Beclin 1 via different domains, allowing formation of a heterotrimeric complex. Strains of measles virus and GAS that bound CD46 induced autophagy in human cells, in a manner dependent on GOPC and Beclin 1 and Cyt-1; isoforms of CD46 containing the Cyt-2 domain could not induce autophagy. CD46-binding GAS strains were also quickly degraded by autophagy within the cell, which was delayed by siRNA-mediated knockdown of the Cyt-1 / GOPC pathway, demonstrating the functional importance of CD46-mediated uptake and xenophagy in restricting intracellular pathogen survival.
Antibody-mediated crosslinking of CD46 also induced autophagy in cultured primary human airway epithelial cells and A549 lung epithelial cells (Tsai et al., 2018). This resulted in increased protection against oxidative stress, which was reversed by the autophagy inhibitor 3-methyladenine. In addition, CD46 ligation enhanced GOPC expression, and limited H2O2-induced increases in cellular pro-IL-1β and NLRP3 content, as well as IL-1β secretion, most likely due to the known role of autophagy in degrading intracellular inflammasome components (Harris et al., 2011; Shi et al., 2012). This shows a potential role for CD46 in protective autophagy in a non-infectious setting, although the physiological ligand for CD46 (C3b) was not investigated in this paper. Curiously, C3 expression has also been found to be protective for human epithelial cells undergoing oxidative stress (Kulkarni et al., 2019), but the direct mechanism for this was not investigated, and autophagy was not implicated. Indeed, the role of C3 was suggested to be intracellular, away from the cell surface location of CD46.
These findings raise further questions as to whether C3b binding, or cross-linking of CD46 by material opsonized with C3b, also induces autophagy. The obvious case of this would be induced by the presence of C3b-opsonised pathogens, in which case xenophagy induction would be beneficial to the host by restriction of pathogen survival. However, some pathogens hijack autophagy for their own benefit (Romano, Gutierrez, Beron, Rabinovitch, & Colombo, 2007), which could also be a cause for selection of these pathogens to bind CD46 directly. Indeed, prolonged autophagy at a later stage of infection has been shown to contribute to the replication of measles virion particles (Richetta et al., 2013).