APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection

Abstract

Double-stranded RNA produced during viral replication and transcription activates both protein kinase R (PKR) and ribonuclease L (RNase L), which limits viral gene expression and replication through host shutoff of translation. In this study, we find that APOBEC3B forms a complex with PABPC1 to stimulate PKR and counterbalances the PKR-suppressing activity of ADAR1 in response to infection by many types of viruses. This leads to translational blockage and the formation of stress granules. Furthermore, we show that APOBEC3B localizes to stress granules through the interaction with PABPC1. APOBEC3B facilitates the formation of protein-RNA condensates with stress granule assembly factor (G3BP1) by protecting mRNA associated with stress granules from RNAse L-induced RNA cleavage during viral infection. These results not only reveal that APOBEC3B is a key regulator of different steps of the innate immune response throughout viral infection but also highlight an alternative mechanism by which APOBEC3B can impact virus replication without editing viral genomes.

RNA recognition by PKR during DNA virus infection

“…While the mechanism by which A3B and PABPC1 stimulates PKR requires further investigation, it was determined that the A3B deaminase activity was not required. 61 The ability of RNA modifications to prevent PKR activation is consistent with the emerging theme that they serve a fundamental role in self-versus nonself-recognition of RNA. Moreover, accumulating evidence suggests that modification enzymes can influence PKR activation in a catalytic-independent manner.…”

“…While ADAR1 functions to avert aberrant activation of PKR by self dsRNAs, another deaminase, apolipoprotein B mRNA‐editing enzyme catalytic polypeptide‐like 3B (A3B) was reported to promote PKR autophosphorylation and translation blockage in cells infected with Sendai virus (SeV) or depleted of ADAR1 61 . A3B was found to form a complex with polyadenylate‐binding protein cytoplasmic 1 (PABPC1) that was essential for the stimulation of PKR.…”

“…A3B was found to form a complex with polyadenylate‐binding protein cytoplasmic 1 (PABPC1) that was essential for the stimulation of PKR. While the mechanism by which A3B and PABPC1 stimulates PKR requires further investigation, it was determined that the A3B deaminase activity was not required 61 …”

Non-canonical contribution of human Dicer helicase domain in antiviral innate immune response

“…Specifically, we could identify among the differentially expressed genes a substantial fraction of targets of key immune transcription factors such as STAT2 and NF-kB. We retrieved and validated the differential expression levels for known antiviral effectors such as PTGS2, APOBEC3B or OAS3 (Jiang et al , 2008; Lehman et al , 2022; Manjunath et al , 2023; Ryman et al , 2002). This observation is reminiscent of other studies that showed that Dicer could be involved in non-RNAi related signaling pathways.…”

Regulatory variants of APOBEC3 genes potentially associate with COVID-19 severity in populations with African ancestry

“…Furthermore, the upregulated expression of APOBEC3B induced by folate de ciency was associated with the inhibition of replication of vesicular stomatitis virus in vitro and in vivo [30]. Recently, APOBEC3B was shown to combine with Poly (A) binding protein cytoplasmic 1 to stimulate protein kinase R (PKR) and overturned the impaired activity of PKR that caused by Sendai virus infection, since stimulation of PKR would shutoff cellular translation thus cutoff viral gene expression [31]. This research hinted APOBEC3B could affect viral infection via not only editing viral genome but also regulating host innate immunity response.…”