IRE1α Regulates Dendritic Cell Function in Response to Viral Infection

By Natalia Gurule, PhD

What is IRE1 alpha?

Inositol- requiring enzyme type 1 alpha (IRE1α) is a serine/threonine kinase that is one of the three transducers within the unfolded protein response (UPR) signaling pathway which becomes activated upon accumulation of misfolded proteins within the endoplasmic reticulum (ER).¹ IRE1α contains two domains, the N- terminal domain that senses misfolded proteins within the ER lumen and the C- terminal domain that signals through serine/threonine kinase and endoribonuclease domains within the cytoplasm to initiate the UPR response.² Mechanistically, IRE1α is known to induce apoptosis and target cytosolic RNAs for degradation upon conditions of ER stress.³ IRE1α-dependent apoptosis is induced through two mechanisms: the first is regulated through alternative splicing of the transcription factor x-box binding protein 1 (XBP1), and the second is via activation of the c-Jun N-terminal kinase (JNK) pathway, which occurs under severe stress.⁴

IRE1α: A major player in cellular response to disease

IRE1 (inositol-requiring enzyme 1 or ERN1) has been implicated in physiological processes and pathogenesis of multiple diseases including cancer, neurodegenerative, inflammatory, and metabolic diseases.^5,6 Many of these diseases are associated with accumulation of misfolded proteins while also exhibiting an increase in IRE1 activity, providing rationale for pharmacological targeting of IRE1α. A study by Tognarelli and colleagues described upregulation of IRE1α activity and downstream XPB1 splicing in dendritic cells (DCs) infected with herpes simplex virus type 2 (HSV-2).⁷ Recent findings show that endonuclease activity of IRE1 was responsible for viability of DCs infected with HSV-2.⁸ Furthermore, they demonstrate that inhibition of IRE1α endonuclease activity in mice infected with HSV enhanced the ability of DCs to migrate to the lymph nodes and activate virus-specific T cell responses.

IRE1α also has a role in modulating susceptibility to host cell apoptosis in response to HSV and vesicular stomatitis virus (VSV). Interestingly, loss of XBP1 in mouse embryonic fibroblasts (MEFs) caused upregulation of IRE1α enzymatic activity.⁹ Using this model, cells infected with either HSV or VSV were not only unable to undergo apoptosis, but viral replication was also increased. A common pharmacologic strategy to inhibit IRE1α activity is to use compounds that block the RNAse enzymatic activity of IRE1α. One such study found using a selective IRE1α nuclease inhibitor sensitized infected cells to apoptosis and decreased viral replication, indicating that RNAse activity of IRE1α is capable of contributing to apoptosis resistance.¹⁰ Taken together, these findings define a functional role for IRE1α in cellular responses to viral infections such as HSV, VSV, and hepatitis C virus (HCV).