Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA

Abstract

Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the innate immune receptors that recognize viral double-stranded RNA (dsRNA) and initiate antiviral immune responses with the potential of triggering systemic inflammation and immunopathology. How the functions of the dsRNA receptors and their downstream effector molecules are coordinately regulated to avoid excessive immune response is poorly understood. We here demonstrate that stress granules (SGs), biomolecular condensates that form in response to various stresses including viral dsRNA1,2, play key roles in regulating dsRNA-triggered immune response. Upon dsRNA stimulation, SGs recruit many innate immune molecules, including RIG-I-like receptors (RLRs), protein kinase R (PKR) and oligoadenylate synthases (OASes), target these molecules and dsRNA for autophagy and limit their functions through sequestration. In the absence of SGs, dsRNA stimulation results in hyperactivation of inflammatory signaling pathways, global translational arrest and bulk RNA degradation, altogether compromising the cellular capacity to restore homeostasis and triggering cell death. In contrast to most dsRNA-induced immune signaling pathways that are hyperactivated in the absence of SGs, a sub-branch of the RLR pathway (IRF3-dependent type I interferon signaling) shows time-dependent changes, where the initial spike in signaling is followed by a significant drop due to increased caspase-dependent negative feedback regulation. This highlights the role of SGs in regulating the delicate balance between the type I interferon pathway and cell death. Altogether, our data suggest that cells utilize SGs as shock absorbers to moderate antiviral innate immune response, thereby allowing cells to guard against its own immune system as well as viruses.

Activation of the mitochondrial unfolded protein response regulates the formation of stress granules

“…SGs can physically contact different membrane-bound organelles, including lysosomes or the ER, and starvation-induced SGs contact with mitochondria in human cells (Amen and Kaganovich, 2021; Lee et al, 2020; Liao et al, 2019). Furthermore, numerous mitochondrial proteins have been associated with SGs (Amen and Kaganovich, 2021; Aoyama-Ishiwatari et al, 2021; Paget et al, 2023). Our study identifies SGs as novel signalling components associated with the mammalian UPRmt and SG dynamics as a key for maintaining mitochondrial function during mitochondrial stress.…”

“…Questions remain as to the functional link between inhibition of SG assembly and mitochondrial homeostasis following UPRmt activation. Several studies support a protective role for SGs, through impairing pro-apoptotic JNK signalling (Arimoto et al, 2008; Kitajima et al, 2023), sequestration of caspases (Fujikawa et al, 2023) or suppressing production of ROS (Park and Shin, 2023; Takahashi et al, 2013) and they have been described as “shock absorbers” dampening excessive innate immune response to viral infection (Paget et al, 2023). In contrast, persistent SGs are implicated in pro-death functions during chronic stress conditions as well as neurodegenerative diseases or tumour chemotherapy (Reineke et al, 2018; Reineke and Neilson, 2019; Schwed-Gross et al, 2022).…”

Autophagy degrades immunogenic endogenous retroelements induced by 5-azacytidine in acute myeloid leukemia

“…While this question will need to be explored in future studies, we surmise that autophagy degrades ERE RNAs instead of degrading their translational product. Indeed, autophagy has been reported to target viral (66) and ERE (34) dsRNA to autophagosomes. Notably, this would explain why CTA MAPs (which do not result from dsRNA) were successfully presented at higher levels after AZA treatment.…”

“…Unexpectedly, we also observed that many GO terms related to protein degradation/catabolism and autophagy were significantly downregulated in these patients. Since ERE RNAs can trigger autophagy (34) and be degraded by the autophagic process (35), we hypothesized that enhanced autophagy in low-ERE expressing blasts could protect them from the deleterious effects that EREs have on their proliferation. This idea was explored in-depth in our next series of experiments.…”

“…Interestingly, this was not observed with DAC, suggesting that autophagy induction is dependent on protein aggregates generation resulting from DNMT2 inhibition. As EREs were previously suggested to trigger autophagy (34), we evaluated whether DAC induced the same EREs as AZA. Using data reported by Pappalardi et al (46), we observed that DAC expressed AZA-induced EREs in a dose-dependent manner (Figure 5B).…”