Hiding in Plain Sight: Formation and Function of Stress Granules During Microbial Infection of Mammalian Cells

Abstract

Stress granule (SG) formation is a host cell response to stress-induced translational repression. SGs assemble with RNA-binding proteins and translationally silent mRNA. SGs have been demonstrated to be both inhibitory to viruses, as well as being subverted for viral roles. In contrast, the function of SGs during non-viral microbial infections remains largely unexplored. A handful of microbial infections have been shown to result in host SG assembly. Nevertheless, a large body of evidence suggests SG formation in hosts is a widespread response to microbial infection. Diverse stresses caused by microbes and their products can activate the integrated stress response in order to inhibit translation initiation through phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). This translational response in other contexts results in SG assembly, suggesting that SG assembly can be a general phenomenon during microbial infection. This review explores evidence for host SG formation in response to bacterial, fungal, and protozoan infection and potential functions of SGs in the host and for adaptations of the pathogen.

Keywords: GCN2; HRI; PERK; PKR; eIF2 alpha; integrated stress response (ISR); stress granules (SG); unfolded protein response (UPR).

FIGURE 1

Integrated stress response (ISR) increases P-eIF2α and induces SGs, but overlaps with the unfolded protein response (UPR) through the activation of PERK. ISR detects ER Stress, dsRNA, heme deprivation and oxidation stress, and amino acid starvation and promote the dimerization and activation of the stress kinases PERK, PKR, HRI, and GCN2, respectively. Once activated, these kinases phosphorylate eIF2α, which stalls translation and promotes the formation of stress granules. P-eIF2α also promotes the selective translation of uORF containing mRNA, including ATF4, CHOP, and GADD34. GADD34 associates with the eIF2α phosphatase PP1 to dephosphorylate eIF2α during stress recovery. The ISR is closely associated with the UPR, connected through PERK. Upon detection of unfolded proteins, ATF6, IRE1, and PERK are all activated, promoting cleavage of ATF6, splicing of XBP1, and the induction of P-eIF2α. Cleaved ATF6 and spliced XBP1 promote the expression of UPR target genes to elicit a response to unfolded protein.

FIGURE 2

Microbial stimuli activate stress kinases in the integrated stress response (ISR) and the unfolded protein response (UPR) pathways. Microorganisms are able to induce the ISR and UPR through a variety of mechanisms. Type III and IV bacterial secretion systems (T3SS and T4SS) promote ER restructuring and the release of microbial effector proteins that can activate PERK and the UPR. PKR can be activated through PKR activating stimuli other than dsRNA. Calcium can be released through quorum sensing molecules and ROS generation, which also induces oxidative stress and protein misfolding, in turn activating the UPR and PERK. Nutrient and iron deprivation may be induced by microbes and their products promoting activation of GCN2 and HRI, respectively.