Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) (PubMed:11779464, PubMed:11175748, PubMed:12637535, PubMed:9637683, PubMed:21317875, PubMed:28128204). In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP (PubMed:21317875). Accumulation of misfolded proteins in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity (PubMed:21317875). The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA (PubMed:11779464, PubMed:24508390, PubMed:21317875). The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes (PubMed:11779464, PubMed:24508390, PubMed:21317875). Acts as an upstream signal for ER stress-induced GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane by modulating the expression and localization of SEC16A (PubMed:21884936, PubMed:28067262). ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] The kinase domain is activated by trans-autophosphorylation following homodimerization (PubMed:12637535, PubMed:9637683). Kinase activity is required for activation of the endoribonuclease domain (PubMed:12637535, PubMed:9637683). Endoribonuclease activity is specifically inhibited by hydroxy-aryl-aldehydes (HAA) (By similarity). Monomer (PubMed:29198525, PubMed:16973740). Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities (PubMed:12637535, PubMed:24508390, PubMed:16973740, PubMed:21317875). Dimer formation is driven by hydrophobic interactions within the N-terminal luminal domains and stabilized by disulfide bridges (PubMed:12637535). Interacts (via the luminal region) with DNAJB9/ERdj4; interaction takes place in unstressed cells and promotes recruitment of HSPA5/BiP (PubMed:29198525). Interacts (via the luminal region) with HSPA5/BiP; HSPA5/BiP is a negative regulator of the unfolded protein response (UPR) that prevents homodimerization of ERN1/IRE1 and subsequent activation of the protein (PubMed:12637535, PubMed:29198525). Interacts with PDIA6, a negative regulator of the UPR; the interaction is direct and disrupts homodimerization (PubMed:24508390). Interacts with DAB2IP (via PH domain); the interaction occurs in a endoplasmic reticulum stress-induced dependent manner and is required for subsequent recruitment of TRAF2 to ERN1/IRE1 (By similarity). Interacts with TAOK3 and TRAF2 (PubMed:11278723). Interacts with RNF13 (PubMed:23378536). Interacts with LACC1 (PubMed:31875558). Interacts (when unphosphorylated) with DDRGK1; interaction is dependent on UFM1 and takes place in response to endoplasmic reticulum stress, regulating ERN1/IRE1-alpha stability (PubMed:28128204). Interacts (via N-terminus) with P4HB/PDIA1; the interaction is enhanced by phosphorylation of P4HB by FAM20C in response to endoplasmic reticulum stress and results in attenuation of ERN1 activity (PubMed:32149426). Ubiquitously expressed. High levels observed in pancreatic tissue. Autophosphorylated following homodimerization. Autophosphorylation promotes activation of the endoribonuclease domain. ADP-ribosylated by PARP16 upon ER stress, which increases both kinase and endonuclease activities. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.