A potential third-order role of the host endoplasmic reticulum as a contact site in interkingdom microbial endosymbiosis and viral infection.

The normal functioning of eukaryotic cells depends on the compartmentalization of metabolic processes within specific organelles. Interactions among organelles, such as those between the endoplasmic reticulum (ER) - considered the largest single structure in eukaryotic cells - and other organelles at membrane contact sites (MCSs) have also been suggested to trigger synergisms, including intracellular immune responses against pathogens. In addition to the ER-endogenous functions and ER-organelle MCSs, we present the perspective of a third-order role of the ER as a host contact site for endosymbiotic microbial non-pathogens and pathogens, from endosymbiont bacteria to parasitic protists and viruses. Although understudied, ER-endosymbiont interactions have been observed in a range of eukaryotic hosts, including protists, plants, algae, and metazoans. Host ER interactions with endosymbionts could be an ER function built from ancient, conserved mechanisms selected for communicating with mutualistic endosymbionts in specific life cycle stages, and they may be exploited by pathogens and parasites. The host ER-'guest' interactome and traits in endosymbiotic biology are briefly discussed. The acknowledgment and understanding of these possible mechanisms might reveal novel evolutionary perspectives, uncover the causes of unexplained cellular disorders and suggest new pharmacological targets.