PRRs detect three types of patterns associated with the macromolecular structure of cytosolic bacteria and PVs: missing-self, aberrant-self, and non-self.
2013-09-19T02:15:46Z (GMT) by
<p>Three examples of PRRs are given to highlight the principles by which the innate immune system discriminates self membranes from PVs and cytosolic bacteria. I) Missing-self: in order to bind to membranes, GKS proteins of the IRG family of GTPases must first exchange GDP for GTP. In the GTP-bound, “activated” state, GKS proteins oligomerize and stably associate with membranes. IRGM proteins residing on self membranes, e.g., on lipid droplets (LDs) or mitochondria, inhibit GKS activation and thus shield self membranes against GKS proteins. PVs formed by microbes like <i>C. trachomatis</i> are devoid of IRGM proteins and therefore permissive for GKS protein binding. II) Aberrant-self: host-derived glycans decorate the plasma membrane as well as the luminal side of vacuoles, including PVs. In disrupted vacuoles, glycans become exposed to the cytosol. Cytosolic Galectin-8 can bind to exposed glycans and subsequently recruit the autophagy adaptor protein NDP52 to these “broken” vacuoles. III) Non-self: the ubiquitin ligase LRSAM1 can directly bind to bacterial surfaces. Once attached to cytosolic bacteria, LRSAM1 polyubiquitinates itself, forming predominantly K6 and K27 linkages. Additionally, LRSAM1 binds to NDP52 to promote autophagic degradation of cytosolic bacteria (xenophagy). Although the three PRRs listed here detect distinct patterns, they are likely to cooperate in immune surveillance. For example, GKS proteins rupture PV membranes and thus induce an aberrant-self pattern in PVs that is recognizable by galectins. Subsequent recruitment of autophagy adaptor proteins may further promote the disintegration of PV membranes, thereby allowing LRSAM1 to bind directly to the disrobed microbe.</p>