Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen (PubMed:2294010, PubMed:23769672, PubMed:23990668, PubMed:28332555). Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5, probably to facilitate the release of DNAJC10/ERdj5 from its substrate (By similarity). Acts as a key repressor of the EIF2AK3/PERK and ERN1/IRE1-mediated unfolded protein response (UPR) (PubMed:11907036, PubMed:1550958, PubMed:19538957, PubMed:36739529).

In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1 (By similarity). Also binds and inactivates EIF2AK3/PERK in unstressed cells (PubMed:11907036). Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1 and EIF2AK3/PERK, allowing their homodimerization and subsequent activation (PubMed:11907036).

Plays an auxiliary role in post-translational transport of small presecretory proteins across endoplasmic reticulum (ER). May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel. Appears to specifically regulate translocation of precursors having inhibitory residues in their mature region that weaken channel gating.

May also play a role in apoptosis and cell proliferation (PubMed:26045166)

Monomer and homooligomer; homooligomerization via the interdomain linker inactivates the chaperone activity and acts as a storage of HSPA5/BiP molecules (By similarity). Interacts with DNAJC1 (via J domain) (By similarity). Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5 (By similarity).

Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX (By similarity). Interacts with TMEM132A and TRIM21 (PubMed:12699405). May form a complex with ERLEC1, OS9, SEL1L and SYVN1 (PubMed:18264092, PubMed:18502753).

Interacts with DNAJC10 (PubMed:12411443, PubMed:23769672). Interacts with DNAJB9/ERdj4; leading to recruit HSPA5/BiP to ERN1/IRE1 (By similarity). Interacts with ERN1/IRE1 (via luminal domain); the interaction takes place following interaction with DNAJB9/ERdj4 and leads to inactivate ERN1/IRE1, the interaction also competitively inhibits ERN1 interaction with MANF (PubMed:36739529).

Interacts directly with MANF (via SAP domain); the interaction inhibits ATP binding to HSPA5/BiP and subsequent nucleotide exchange (By similarity). Interacts with EIF2AK3/PERK (via luminal domain); interaction leads to inactivate EIF2AK3/PERK (PubMed:11907036, PubMed:36739529). Interacts with MX1 (By similarity).

Interacts with METTL23 (PubMed:23349634). Interacts with CEMIP; the interaction induces calcium leakage from the endoplasmic reticulum and cell migration (PubMed:23990668). Interacts with PCSK4 form; the interaction takes place in the endoplasmic reticulum (PubMed:21080038).

Interacts with CIPC (PubMed:26657846). Interacts with CCDC88B (via C-terminus); the interaction opposes ERN1-mediated JNK activation, protecting against apoptosis (PubMed:21289099). Interacts with INPP5K; necessary for INPP5K localization at the endoplasmic reticulum (PubMed:26940976).

Interacts with MANF; the interaction is direct (PubMed:22637475). Interacts with LOXL2; leading to activate the ERN1/IRE1-XBP1 pathway of the unfolded protein response (PubMed:28332555). Interacts with CLU under stressed condition; interaction increases CLU protein stability; facilitates its retrotranslocation and redistribution to the mitochondria; cooperatively suppress stress-induced apoptosis by stabilizing mitochondrial membrane integrity (PubMed:22689054).

Interacts with CCDC47 (By similarity). Interacts with CLN3 (Probable). Interacts with ELAPOR1; may regulate the function of HSPA5 in apoptosis and cell proliferation (PubMed:26045166).

Interacts with CASP7 (PubMed:26045166). Interacts with ILDR2; the interaction stabilizes ILDR2 expression (By similarity). Interacts with ADAM7 (By similarity)

(Microbial infection) Interacts with Japanese encephalitis virus envelope protein E

(Microbial infection) Interacts with R.delemar invasin CotH3 on the surface of nasal epithelial cells (PubMed:24355926, PubMed:32487760). Interacts with R.delemar invasin CotH2 (PubMed:24355926)

(Microbial infection) Interacts with Zika virus envelope protein E and non-structural protein 1 in a chaperone-client manner

The interdomain linker regulates the chaperone activity by mediating the formation of homooligomers. Homooligomers are formed by engagement of the interdomain linker of one HSPA5/BiP molecule as a typical substrate of an adjacent HSPA5/BiP molecule. HSPA5/BiP oligomerization inactivates participating HSPA5/BiP protomers.

HSPA5/BiP oligomers probably act as reservoirs to store HSPA5/BiP molecules when they are not needed by the cell. When the levels of unfolded proteins rise, cells can rapidly break up these oligomers to make active monomers

• Unknown disease