HSPA5

The protein encoded by this gene is a member of the heat shock protein 70 (HSP70) family. This protein localizes to the lumen of the endoplasmic reticulum (ER) where it operates as a typical HSP70 chaperone involved in the folding and assembly of proteins in the ER and is a master regulator of ER homeostasis. During cellular stress, as during viral infection or tumorogenesis, this protein interacts with the transmembrane stress sensor proteins PERK (protein kinase R-like endoplasmic reticulum kinase), IRE1 (inositol-requiring kinase 1), and ATF6 (activating transcription factor 6) where it acts as a repressor of the unfolded protein response (UPR) and also plays a role in cellular apoptosis and senescence. Elevated expression and atypical translocation of this protein to the cell surface has been reported in viral infections and some types of cancer cells. At the cell surface this protein may facilitate viral attachment and entry to host cells. This gene is a therapeutic target for the treatment of coronavirus diseases and chemoresistant cancers.

Heat Shock Protein Family A (Hsp70) Member 5

BIP; GRP78; HEL-S-89n

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 ERN1/IRE1-mediated unfolded protein response (UPR) (PubMed:1550958, PubMed:19538957).

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).

Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1, allowing homodimerization and subsequent activation of ERN1/IRE1 (By similarity).

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).

(Microbial infection) Plays an important role in viral binding to the host cell membrane and entry for several flaviruses such as Dengue virus, Zika virus and Japanese encephalitis virus (PubMed:33432092, PubMed:15098107, PubMed:28053106).

Acts as a component of the cellular receptor for Dengue virus serotype 2/DENV-2 on human liver cells (PubMed:15098107).

(Microbial infection) Acts as a receptor for CotH proteins expressed by fungi of the order mucorales, the causative agent of mucormycosis, which plays an important role in epithelial cell invasion by the fungi (PubMed:24355926, PubMed:20484814, PubMed:32487760).

Acts as a receptor for R.delemar CotH3 in nasal epithelial cells, which may be an early step in rhinoorbital/cerebral mucormycosis (RCM) disease progression (PubMed:32487760).

Cellular response to antibiotic Source: Ensembl
Cellular response to calcium ion Source: Ensembl
Cellular response to cAMP Source: Ensembl
Cellular response to gamma radiation Source: Ensembl
Cellular response to glucose starvation Source: UniProtKB
Cellular response to interleukin-4 Source: Ensembl
Cellular response to manganese ion Source: Ensembl
Cellular response to nerve growth factor stimulus Source: Ensembl
Cellular response to unfolded protein Source: GO_Central
Cellular response to xenobiotic stimulus Source: Ensembl
Cerebellar Purkinje cell layer development Source: Ensembl
Cerebellum structural organization Source: Ensembl
Chaperone cofactor-dependent protein refolding Source: GO_Central
Endoplasmic reticulum unfolded protein response Source: GO_Central
ER overload response Source: Ensembl
Luteolysis Source: Ensembl
Maintenance of protein localization in endoplasmic reticulum Source: UniProtKB
Negative regulation of apoptotic process Source: UniProtKB
Negative regulation of IRE1-mediated unfolded protein response Source: UniProtKB
Negative regulation of protein-containing complex assembly Source: UniProtKB
Negative regulation of transforming growth factor beta receptor signaling pathway Source: Ensembl
Neuron apoptotic process Source: Ensembl
Neuron differentiation Source: Ensembl
Positive regulation of cell migration Source: UniProtKB
Positive regulation of neuron projection development Source: Ensembl
Positive regulation of protein ubiquitination Source: Ensembl
Positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
Posttranslational protein targeting to membrane, translocation Source: UniProtKB
Protein folding in endoplasmic reticulum Source: ParkinsonsUK-UCL
Protein refolding Source: GO_Central
Regulation of ATF6-mediated unfolded protein response Source: ParkinsonsUK-UCL
Regulation of IRE1-mediated unfolded protein response Source: ParkinsonsUK-UCL
Regulation of PERK-mediated unfolded protein response Source: ParkinsonsUK-UCL
Regulation of protein folding in endoplasmic reticulum Source: BHF-UCL
Response to cocaine Source: Ensembl
Response to methamphetamine hydrochloride Source: Ensembl
Stress response to metal ion Source: Ensembl
Substantia nigra development Source: UniProtKB
Toxin transport Source: Ensembl
Ubiquitin-dependent ERAD pathway Source: GO_Central

Endoplasmic reticulum lumen; Cytoplasm; Melanosome; Cell surface. Identified by mass spectrometry in melanosome fractions from stage I to stage IV (PubMed:12643545). Localizes to the cell surface of epithelial cells in response to high levels of free iron (PubMed:20484814, PubMed:24355926, PubMed:27159390).

Autoantigen in rheumatoid arthritis.

AMPylated by FICD (PubMed:25601083). In unstressed cells, AMPylation at Thr-518 by FICD inactivates the chaperome activity: AMPylated form is locked in a relatively inert state and only weakly stimulated by J domain-containing proteins (By similarity). In response to endoplasmic reticulum stress, de-AMPylation by the same protein, FICD, restores the chaperone activity (By similarity).