Table 2.

Partners in regulating IREα endoribonuclease activity.

IRE1α Binding Partner	Function of IRE1α Binding Partner	Functional Implication	References
NMIIB (Non muscle myosin IIB)	A Cytoskeleton myosin protein	Interacts with IRE1α and regulates its oligomerization and activation. In addition, recruits other regulatory molecules to oligomerized foci.	[136]
AIP1	Apoptotic signaling transducer	AIP1-IRE1α association enhances IRE1 dimerization and its downstream JNK/XBP1 activation.	[137]
PDIA6	Chaperonic protein of ER that inhibits aggregation of misfolded proteins	PDIA6 attenuates the activity of IRE1α. PDIA6, an ER resident protein disulfide isomerase. Negatively regulates IRE1α by binding to its luminal domain at cysteine 148, if it is oxidized, IRE1α will be activated. PDIA6-deficient cells hyperrespond to ER stress with sustained autophosphorylation of IRE1α and increased XBP1s, pJNK.	[138]
PTP-1B	Protein-tyrosine phosphatase 1B	In the absence of PTP-1B, ER stress-induced IRE1α downstream activities were impaired, especially XBP1 splicing and JNK activation.	[139]
UbD	Ubiquitin-like modifier family member	UbD regulates IRE1α/c-Jun N-terminal kinase signaling pathway. It provides a negative feedback on cytokine-induced activation of the IRE1α/JNK pro-apoptotic pathway in cytokine-exposed beta cells, but did not change cytokine-induced XBP1 splicing.	[140]
TMBIM6	ER localized antiapoptotic protein, also known as Bax inhibitor-1 (BI-1)	This has been implicated in the negative modulation of XBP1 splicing activity through interacting with a cytosolic region of IRE1α.	[141]
Hsp47	Heat shock protein	Hsp47 binds directly to the IRE1 ER luminal domain with high affinity, eliminating BiP from the complex to allow IRE1α oligomerization for optimal signaling.	[142]
HSP72	Heat shock protein	Overexpression of HSP72, survival effect of HSP72 under ER stress is mediated by enhanced XBP1splicing and its target genes. Regulation of UPR by HSP72 is by formation of stable protein complex with IRE1α.	[143]
HSP90	Heat shock protein	HSP90 stabilizes IRE1α by preventing the proteasomal degradation, and treatment of HSP90 inhibitor decreases IRE1α protein stability.	[144]
JIK	c-Jun N-terminal inhibitory kinase	IRE1α and TRAF2 complex induce apoptotic signal through c-Jun N-terminal kinase pathway and activation of caspase-12.	[145]
JAB1	Jun activation domain-binding protein-1	Mutant JAB1 down-regulates the UPR signaling pathway through tight binding with IRE1alpha.	[146]
RACK1	Receptor for activated C-kinase 1	Interacts with IRE1α and plays a role in dephosphorylation of IRE1α by protein phosphatase (PP2A). Furthermore, IRE1α and RACK1 association may contribute in this process of antiapoptosis by phosphorylating AMPK and Bcl-2 through enhancing autophagy.	[147,148]
Nck	SH2/SH3 adaptor protein	Nck and IRE1α association in immune T cells have a critical role in ER-stressed activation of MAPK pathway and cell survival.	[149]
RNF13	RING finger protein	RNF13 knockdown cells showed resistance to apoptosis and JNK activation triggered by ER stress. Conversely, overexpression of RNF13 induces JNK activation and caspase-dependent apoptosis.	[150]
PARP16/ARTD15	Poly ADP-ribose polymerases/ADP-ribosyl transferase D proteins	PARP16 is an upstream regulator, and modification increases its kinase and the endonuclease activity of IRE1α.	[151]
BAX/BAK	Pro-apoptotic protein	BAX and BAK directly interact at cytosolic domain of IRE1α during stress condition and promote the stabilized IRE1α activity.	[152]
BIM/PUMA	Pro-apoptotic protein	BIM and PUMA have also been linked to IRE1α regulation by direct binding with IRE1α via their BH3 domain in stress-dependent manner. Cells deficient in both BIM and PUMA exhibited reduced splicing of XBP-1 and RIDD.	[153]
NMI	N-Myc interactor	Interacts and modulates IRE1α especially in pancreatic beta cell. It negatively regulates the IRE1α-mediated JNK activation and further the cell death.	[154]
DCR2	Dose-dependent cell-cycle regulator 2	Physically interacts with phosphorylated IRE1α and causes dephosphorylation and IRE1 deactivation.	[155]
Cab45S	A member of the CREC family	Negatively regulates RNAse activity of IRE1α and prevents more spliced forms of X-box-binding protein 1 mRNA at the early stage of stress and further phosphorylation of c-Jun N-terminal kinase induced apoptosis.	[156]
SYVN1	Functions in ER-associated degradation process	Coexpression of IRE1 and SYVN1 increased IRE1 degradation and ubiquitination.	[157]
DDRGK1	DDRGK domain-containing protein 1	Interaction of DDRGK1 with IRE1α counteracts ubiquitination and subsequently inhibits the ERAD-mediated degradation of IRE1α.	[55]
PRKCSH	Protein kinase C substrate 80K-H	In ER stress condition, PRKCH steps up ER stress-mediated autophosphorylation and oligomerization of IRE1 through mutual interaction followed by XBP1 splicing and MAPK activation which contribute to tumorigenesis.	[158]
Sigma-1 receptor	Unique ligand-regulated molecular chaperone in the ER.	Under ER stress conditions, interacts with and stabilizes IRE1α and enhances cell survival through prolonged activation of the IRE1α-XBP1 pathway, especially in cancer cell survival.	[159]
Sec61	Channel-forming translocon complex	Forms a hetero-oligomeric complex with IRE1α upon ER stress. It recruits XBP1u and aids in splicing. The Sec61-IRE1α complex defines the extent of IRE1α activity and may determine cell fate decisions during ER stress conditions.	[160,161]
Fortilin	Pro-survival molecule	Interacts with the cytoplasmic domain of IRE1α, inhibits both kinase and RNase activities, and protects cells from apoptotic cell death.	[162]
Filamin A	Actin crosslinking factor involved in the remodeling of cytoskeletons	Through a novel domain located at the distal C-terminal region, monomeric IRE1α interacts physically with Filamine A. A pro-migratory stimulus causes dimerization of IRE1α, increasing Filamin A binding and PKCα recruitment. Phosphorylation of Filamine A by PKCα at S2152 improves actin cytoskeleton remodeling and cell migration in different animal species	[163]
ABL kinase	Tyrosine-protein kinase	ABL kinase interaction enhances IRE1α RNase activity and potentiates its apoptosis signaling pathway.	[164]