Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) (PubMed:11850408, PubMed:25164867). In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP. Accumulation of misfolded protein 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:25164867). The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA (PubMed:11850408, PubMed:25164867). The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes (PubMed:11850408, PubMed:25164867). 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 (By similarity). 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. Kinase activity is required for activation of the endoribonuclease domain (PubMed:25164867). Endoribonuclease activity is specifically inhibited by hydroxy-aryl-aldehydes (HAA) MKC9989, OICR464 and OICR573 (PubMed:25164867). Monomer (By similarity). Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities (PubMed:25164867). Dimer formation is driven by hydrophobic interactions within the N-terminal luminal domains and stabilized by disulfide bridges (PubMed:25164867). Interacts (via the luminal region) with DNAJB9/ERdj4; interaction takes place in unstressed cells and promotes recruitment of HSPA5/BiP (By similarity). 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 (By similarity). Interacts with PDIA6, a negative regulator of the UPR; the interaction is direct and disrupts homodimerization (By similarity). 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 (PubMed:18281285). Interacts with TAOK3 and TRAF2 (By similarity). Interacts with RNF13 (By similarity). Interacts with LACC1 (By similarity). Interacts (when unphosphorylated) with DDRGK1; interaction is dependent on UFM1 and takes place in response to endoplasmic reticulum stress, regulating ERN1/IRE1-alpha stability (By similarity). 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 (By similarity). Ubiquitously expressed. High levels in thymus, liver and lung. In the brain, preferentially expressed in cortical, hippocampal and olfactory neurons. 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.