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

Abstract

Summary 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.

The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy

“…In higher eukaryotic cells including fungus, animals, and plants, the ER is considered the largest intracellular organelle, consisting of the outer nuclear envelope, and an intricate network of tubules and cisternae, that extend throughout the cytoplasm ( Almeida, 2021 ). Morphologically, the ER of trypanosomatids is a highly dynamic organelle, a mandatory requirement to perform a plethora of essential functions for parasite survival.…”

“…From the functional perspective the ER of Trypanosomatids, like mammalian cells, may be classified in three hierarchic orders, as proposed by Almeida (2021) ( Figure 3 ). The “first-order” comprises the major traditional endogenous roles of ER, i.e., the biosynthesis, folding and transport of secretory proteins, intracellular site for Ca 2+ storage, synthesis of cellular lipids and sterols, carbohydrate metabolism and biotransformation.…”

“…The “first-order” comprises the major traditional endogenous roles of ER, i.e., the biosynthesis, folding and transport of secretory proteins, intracellular site for Ca 2+ storage, synthesis of cellular lipids and sterols, carbohydrate metabolism and biotransformation. The second-order role of the ER is regarding the way by which this organelle works as an “exchange station” establishing physical membrane contact sites (MCSs) with other organelles, notably with mitochondria, lipid droplets, and plasma membrane ( Soto-Heredero et al., 2017 ; Almeida and Amaral, 2020 ; Almeida, 2021 ). The higher complexity of ER is not circumscribed to their endogenous functions.…”

“…In this regard, in the third-order, the ER can be considered as a host contact site for endosymbiotic pathogenic and non-pathogenic bacteria, parasitic protists, and viruses. In higher eukaryotic cells, these interactions with endosymbionts might be an ancient and conserved ER mechanism, selected for communicating with mutualistic endosymbionts in specific life cycle stages, being further exploited by pathogens ( Almeida, 2021 ).…”

“… Schematic model of different functional niches of ER in Trypanosomatids based on Almeida (2021) model of a first, second and-third-order functional hierarchy for higher eukaryotic cells. The first-order functions are related to endogenous functions of the ER.…”