# Dynamic Modulation of IRE1α-XBP1 Signaling by Adenovirus

## TL;DR

Adenovirus manipulates a key cell stress pathway to support its replication while evading host defenses.

## Contribution

The study reveals a novel antiviral mechanism involving IRE1α de-repression and XBP1 suppression by adenovirus.

## Key findings

- HAdV5 activates IRE1α but blocks the production of XBP1s post-transcriptionally.
- p53 elimination by HAdV5 leads to IRE1α de-repression, potentially as an antiviral response.
- Adenovirus evades host control by co-opting IRE1α and suppressing XBP1s to support its replication.

## Abstract

The abundant production of foreign proteins and nucleic acids during viral infection elicits a variety of stress responses in host cells. Viral proteins that accumulate in the endoplasmic reticulum (ER) can trigger the unfolded protein response (UPR), a coordinated signaling program that culminates in the expression of downstream genes that collectively restore protein homeostasis. The model pathogen adenovirus serotype 5 (HAdV5) activates the UPR via the signaling axis formed by inositol-requiring enzyme type 1 (IRE1α) and the X-box binding protein 1 (XBP1), a transcription factor required for immune function. Recent studies have suggested that IRE1α-XBP1 activity supports adenovirus replication. Here, we show that HAdV5 exerted opposing effects on IRE1α and XBP1. IRE1α was activated in response to HAdV5, but the production of the XBP1 isoform, XBP1s, was post-transcriptionally blocked. The tumor suppressor p53, which is eliminated by HAdV5 after infection, inhibited IRE1α activation. The de-repression of IRE1α following the degradation of p53 conceivably reflects a novel antiviral mechanism, which HAdV5 ultimately evades by co-opting IRE1α and suppressing XBP1s. Our findings illustrate the opposing mechanisms used by adenoviruses and their host cells to exert control over the UPR, a critical determinant of cell fate.