Affinage

Showing DNAJC3 — P58IPK is a alias.

DNAJC3

DnaJ homolog subfamily C member 3 · UniProt Q13217

Length
504 aa
Mass
57.6 kDa
Annotated
2026-06-09
76 papers in source corpus 26 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAJC3/P58(IPK) is a DnaJ co-chaperone that operates at the interface of protein folding and translational control during the unfolded protein response, acting as a negative-feedback regulator that protects secretory cells from ER-stress-induced apoptosis (PMID:12601012, PMID:15793246). As a J-domain co-chaperone, it stimulates the ATPase activity of Hsp70/Hsc70 (PMID:9920933) and, in the ER lumen, associates with BiP to drive productive folding of secretory clients, including selective engagement of misfolded proinsulin (PMID:17567950, PMID:42224595). Structurally it is an elongated monomer of nine TPR motifs arranged in three subdomains plus a C-terminal J domain, with a conserved hydrophobic patch in TPR subdomain I that binds misfolded substrates positioned ~100 Å from the J-domain HPD motif, allowing simultaneous engagement of client and BiP (PMID:20184891, PMID:21799829). At the Sec61 translocon it recruits HSP70 to the cytosolic face and directs proteasomal co-translocational degradation of polypeptides delayed during import (PMID:16923392, PMID:19561072). In parallel, P58(IPK) is transcriptionally induced during ER stress through ERSE/ATF6 and attenuates eIF2α phosphorylation by binding and inhibiting the eIF2α kinases PERK in the ER and PKR in the cytoplasm, the latter through its TPR6 domain and independently of classical J-domain activity (PMID:12446838, PMID:12601012, PMID:8910500, PMID:11939789). This dampening of PERK–eIF2α–CHOP signaling limits oxidative stress and apoptosis, and its loss in mice causes beta-cell apoptosis and diabetes that is rescued by CHOP deletion or antioxidants (PMID:15793246, PMID:25795214). Through PKR inhibition P58(IPK) also restrains dsRNA-induced apoptosis and NLRP3 inflammasome/IL-1β activation, and is co-opted by influenza nucleoprotein to suppress antiviral PKR signaling (PMID:10373525, PMID:27113095, PMID:21698289).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1996 High

    Established which protein domains are necessary for P58(IPK) to inhibit the antiviral kinase PKR and stimulate translation, mapping function to discrete modules before the protein's chaperone identity was known.

    Evidence Deletion mutagenesis with in vitro PKR assays and a SEAP translation reporter in COS-1 cells

    PMID:8910500

    Open questions at the time
    • Did not establish how TPR6 contacts PKR structurally
    • Did not address ER or chaperone functions
  2. 1999 High

    Defined P58(IPK) as a regulated co-chaperone whose PKR-inhibitory activity is switched on by dissociation from Hsp40, linking its activation to viral infection.

    Evidence Co-IP, ATPase activity assays, and dissociation experiments in influenza-infected cells

    PMID:9920933

    Open questions at the time
    • Mechanism of the Hsp40-controlled inactive complex not structurally resolved
    • Viral trigger for dissociation not yet identified
  3. 1999 High

    Showed P58(IPK) protects cells from apoptosis through both PKR-dependent (dsRNA/eIF2α/NF-κB) and PKR-independent (TNF-α) routes, broadening its role beyond translational control.

    Evidence Wild-type vs ΔTPR6 stable NIH 3T3 lines with eIF2α, NF-κB, and apoptosis readouts

    PMID:10373525

    Open questions at the time
    • PKR-independent antiapoptotic mechanism not defined
  4. 2002 High

    Separated P58(IPK)'s translational/PKR functions from canonical J-domain chaperone activity, showing the HPD motif is dispensable for PKR inhibition yet functionally interchangeable with bacterial/yeast J domains.

    Evidence HPD point mutagenesis, cross-species J-domain rescue, Hsc70 ATPase and mammalian translation assays

    PMID:11939789

    Open questions at the time
    • How a functional J domain is used physiologically when not required for PKR inhibition
  5. 2002 High

    Identified P58(IPK) as an ER-stress-induced PERK inhibitor, extending its kinase-attenuating role from the cytoplasm to the ER UPR.

    Evidence ERSE reporter, PERK Co-IP, and p-eIF2α/BiP/CHOP readouts in overexpressing and mutant cells

    PMID:12446838

    Open questions at the time
    • Direct kinase-domain contacts with PERK not mapped
  6. 2002 High

    Revealed negative regulation of P58(IPK) itself via P52(rIPK) binding to TPR7, defining an inhibitory layer adjacent to the PKR-binding TPR motif.

    Evidence Domain-mapped binding assays, Co-IP, and eIF2α/cell-growth readouts

    PMID:12269832

    Open questions at the time
    • Physiological conditions controlling P52(rIPK) engagement unclear
  7. 2003 High

    Placed P58(IPK) as an ATF6-induced negative-feedback inhibitor of the PERK–eIF2α–ATF4 axis, defining its position in the late UPR.

    Evidence Microarray, overexpression and siRNA knockdown with p-eIF2α/ATF4/Gadd153 readouts

    PMID:12601012

    Open questions at the time
    • Timing/kinetics of feedback relative to other UPR arms not quantified
  8. 2005 High

    Demonstrated in vivo that P58(IPK) loss drives beta-cell apoptosis and diabetes, establishing its physiological role as a feedback brake on ER-stress apoptosis in secretory cells.

    Evidence P58(IPK)-null mice with glucose/insulin measures, histopathology, TUNEL, and islet expression arrays

    PMID:15793246

    Open questions at the time
    • Did not pinpoint which downstream signal (PERK vs PKR) causes the apoptosis
  9. 2006 High

    Localized P58(IPK) action to the Sec61 translocon, where it recruits HSP70 and directs proteasomal degradation of stalled translocating proteins, defining a quality-control function distinct from kinase inhibition.

    Evidence Sec61 Co-IP, HSP70 recruitment, nascent-chain crosslinking, proteasome inhibitors, and P58(IPK)-/- mice

    PMID:16923392

    Open questions at the time
    • Relative contribution of translocon vs luminal pools to physiology unresolved
  10. 2006 High

    Used genetic epistasis to show P58(IPK) regulates influenza translation specifically through PKR, not PERK, distinguishing its two kinase targets.

    Evidence P58(IPK)-/-, PKR-/-, PERK-/- MEFs with viral protein labeling and eIF2α assays

    PMID:17166899

    Open questions at the time
    • Context determining PKR vs PERK preference not defined
  11. 2007 High

    Resolved the apparent topological paradox by demonstrating an ER-lumenal P58(IPK) pool bound to BiP that promotes secretory-protein maturation, identifying luminal folding capacity as the basis of stress sensitivity in knockouts.

    Evidence Fractionation, Co-IP with BiP and nascent secretory client, overexpression and in vitro translocation assays in p58-/- cells

    PMID:17567950

    Open questions at the time
    • Mechanism partitioning P58(IPK) between cytosol and ER lumen unknown
  12. 2009 Medium

    Linked P58(IPK) overexpression to co-translocational/preemptive proteasomal degradation of unstructured ER-targeted polypeptides, refining its quality-control specificity.

    Evidence ER-targeted reporters of varying structure with proteasome inhibitors and translocation measures

    PMID:19561072

    Open questions at the time
    • Relies on overexpression; endogenous contribution not established
    • Substrate-selection rules for unstructured domains unclear
  13. 2009 Medium

    Identified GRP78va as an antagonist of P58(IPK)'s PERK inhibition, adding a regulatory node in leukemic cells.

    Evidence GRP78va siRNA knockdown, Co-IP with P58(IPK), and PERK signaling assays

    PMID:19718440

    Open questions at the time
    • Single primary binding method without reciprocal validation
    • Generality beyond leukemic context untested
  14. 2010 High

    Provided genetic proof of P58(IPK)'s co-chaperone action on BiP's nucleotide cycle, showing that removing P58(IPK) rescues Sil1-loss neurodegeneration.

    Evidence Sil1-/- × Dnajc3-/- double-KO mice with ER-stress and Purkinje cell readouts

    PMID:19801575

    Open questions at the time
    • Quantitative effect of P58(IPK) on BiP ATPase cycle in vivo not measured
  15. 2010 High

    Defined the atomic architecture of the TPR region and the hydrophobic patch in subdomain I needed for misfolded-protein binding, giving a structural basis for chaperone activity.

    Evidence 2.5 Å crystal structure with ELISA chaperone assays and structure-based mutagenesis

    PMID:20184891

    Open questions at the time
    • Substrate-bound structure not determined
  16. 2010 Medium

    Showed influenza co-opts P58(IPK) through accessory factors—MK2/MK3-recruited complexes and M2 protein—to modulate PKR, revealing virus-specific tuning of the axis.

    Evidence Co-IP, MK2/MK3 KO and siRNA, Y2H, GST pulldown, and PKR phosphorylation assays

    PMID:20484669 PMID:21204021

    Open questions at the time
    • Opposite effects of complexes (inhibition vs activation) not mechanistically reconciled
    • Single-lab findings
  17. 2011 High

    Determined the full elongated human P58(IPK) structure, positioning the J-domain HPD ~100 Å from the substrate site to argue for simultaneous client and BiP engagement.

    Evidence 3.0 Å crystal structure of human protein

    PMID:21799829

    Open questions at the time
    • No co-structure with BiP or substrate to confirm the dual-engagement model
  18. 2011 High

    Identified influenza nucleoprotein as the viral factor that activates P58(IPK)-mediated PKR inhibition by dissociating it from Hsp40.

    Evidence Yeast two-hybrid, reciprocal Co-IP, co-localization, and NP siRNA with PKR/IFN-β readouts

    PMID:21698289

    Open questions at the time
    • Structural basis of NP-induced Hsp40 dissociation unknown
  19. 2013 High

    Showed P58(IPK) attenuates the PERK–CHOP arm to let tumor cells survive glucose-limited ER stress, framing it as a barrier-overcoming factor in malignancy.

    Evidence CHOP deletion in K-ras(G12V) lung cancer mice with UPR/glucose-flux analysis

    PMID:23395000

    Open questions at the time
    • Direct requirement of P58(IPK) for tumorigenesis not isolated from CHOP genetics
  20. 2013 Medium

    Demonstrated synthetic embryonic lethality of p58(IPK) with ATF6α, showing the UPR compensates for impaired ER folding during development.

    Evidence Atf6α-/- × p58(IPK)-/- double-KO embryonic viability and histology

    PMID:24275136

    Open questions at the time
    • Mechanistic basis of lethality beyond viability not pursued
    • Single lab
  21. 2015 High

    Placed oxidative stress as a proximal apoptotic signal downstream of P58(IPK) loss in beta cells, with CHOP deletion, chemical chaperone, or antioxidants restoring function.

    Evidence P58(IPK)-/- mice with CHOP-deletion and pharmacological rescues, beta-cell and MafA readouts

    PMID:25795214

    Open questions at the time
    • Source of oxidative stress downstream of ER stress not pinpointed
  22. 2016 High

    Connected P58(IPK) to innate immunity by showing it restrains NLRP3 inflammasome and IL-1β through direct PKR binding in macrophages.

    Evidence P58(IPK) KO BMDMs with PKR inhibitor/overexpression rescue, Co-IP, caspase-1 and IL-1β readouts

    PMID:27113095

    Open questions at the time
    • Whether ER-localized vs cytosolic P58(IPK) mediates inflammasome control unclear
  23. 2016 Medium

    Established substrate selectivity by showing P58(IPK) binds misfolded Akita proinsulin but not wild-type, supporting recognition of nonnative clients.

    Evidence Reciprocal Co-IP of WT vs Akita proinsulin in two beta-cell lines with MS identification

    PMID:26947243

    Open questions at the time
    • No mutagenesis or reconstitution to define the recognition determinant
  24. 2026 High

    Demonstrated P58(IPK) is a required component of endogenous BiP folding complexes for productive proinsulin folding, integrating its co-chaperone role into native tissue physiology.

    Evidence Endogenous BiP complex pulldown from islet beta cells via engineered mouse with proinsulin folding assays

    PMID:42224595

    Open questions at the time
    • Stoichiometry and order of cochaperone assembly on BiP not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How P58(IPK) is partitioned and switched between its cytosolic kinase-inhibitory, translocon-associated, and ER-luminal folding functions—and how these are coordinated in human disease—remains unresolved.
  • No structural model of P58(IPK)–PKR or P58(IPK)–PERK complexes
  • Determinants of cytosol/ER partitioning unknown
  • No timeline evidence of a human Mendelian disease mutation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0044183 protein folding chaperone 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005829 cytosol 3
Pathway
R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-5357801 Programmed Cell Death 2
Partners
DNAJB1EIF2AK2EIF2AK3HSPA5HSPA8HYOU1PRKRIRSEC61
Complex memberships
BiP/Hsp70 ER folding complexP58(IPK)-Hsp40-Hsc70 co-chaperone complexSec61 translocon-associated complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 P58(IPK) is activated during influenza virus infection by promoting dissociation of Hsp40 (hsp40) from P58(IPK). Under normal conditions, P58(IPK) exists in an inactive complex with hsp40. Upon influenza infection, hsp40 dissociates, freeing P58(IPK). Additionally, P58(IPK) forms a trimeric complex with hsp40 and hsp/Hsc70, and like other J-domain proteins, P58(IPK) stimulates the ATPase activity of Hsc70, establishing P58(IPK) as a co-chaperone that directs hsp/Hsc70 activity. Co-immunoprecipitation, ATPase activity assay, dissociation/activation assays in influenza-infected cells The Journal of biological chemistry High 9920933
1996 P58(IPK) inhibition of PKR and stimulation of protein synthesis in vivo requires two specific domains: the DnaJ similarity region at the C-terminus (amino acids 391–504) and the tetratricopeptide repeat 6 (TPR6) domain (amino acids 222–255). Variants lacking either domain fail to stimulate translation or block PKR activity in vitro. Transfection analysis with deletion mutants, in vitro PKR inhibition assays, reporter gene (SEAP) translation assays in COS-1 cells The Journal of biological chemistry High 8910500
1999 P58(IPK) suppresses PKR-dependent eIF2α phosphorylation and NF-κB activation induced by dsRNA, protecting cells from dsRNA-induced apoptosis via a mechanism requiring the TPR6 domain (PKR-binding). Additionally, P58(IPK) suppresses TNF-α-induced apoptosis independently of its PKR-inhibitory function, indicating a broader antiapoptotic role. Stable NIH 3T3 cell lines expressing wild-type or ΔTPR6 P58(IPK); treatment with dsRNA or TNF-α; measurement of eIF2α phosphorylation, NF-κB activation, and apoptosis Molecular and cellular biology High 10373525
2002 P58(IPK) inhibition of PKR kinase activity and stimulation of mRNA translation does not require classical J-domain function (HPD motif). HPD point mutations abolish J-domain ATPase-stimulatory activity toward Hsp70 but do not prevent PKR inhibition or support of mRNA translation in mammalian cells. However, the P58(IPK) J domain can substitute functionally for J domains of bacterial DnaJ and yeast Ydj1 in growth rescue assays. Site-directed mutagenesis of HPD motif; yeast and E. coli J-domain functional rescue assays; Hsc70 ATPase activity assay; mammalian cell translation assays Biochemistry High 11939789
2002 P58(IPK) is transcriptionally induced during ER stress via an ER stress-response element (ERSE) in its promoter. P58(IPK) interacts with and inhibits the ER-localized eIF2α kinase PERK. Overexpression of P58(IPK) reduces eIF2α phosphorylation during ER stress, while P58(IPK)-mutant cells show elevated eIF2α phosphorylation and increased BiP and CHOP expression, consistent with prolonged PERK signaling. ERSE promoter reporter assay; co-immunoprecipitation of P58(IPK) with PERK; Western blot for p-eIF2α in overexpressing and mutant cells; gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 12446838
2002 P52(rIPK) interacts with P58(IPK) through its 114-amino-acid charged domain binding specifically to TPR domain 7 of P58(IPK), the domain adjacent to the TPR motif required for PKR interaction. This interaction inhibits P58(IPK) function and its regulation of PKR activity, eIF2α phosphorylation, and cell growth. P52(rIPK) and P58(IPK) form a stable intracellular complex during acute cytoplasmic stress. Domain mapping with deletion constructs; in vitro binding assays; co-immunoprecipitation; cell growth and eIF2α phosphorylation assays Biochemistry High 12269832
2003 P58(IPK) is induced during ER stress and functions as a negative feedback inhibitor of the PERK–eIF2α–ATF4 pathway. Overexpression of P58(IPK) inhibits eIF2α phosphorylation and reduces ATF4 and Gadd153 accumulation; silencing P58(IPK) enhances eIF2α phosphorylation and increases ATF4 and Gadd153. Induction of P58(IPK) during ER stress is mediated via ATF6. Microarray analysis; overexpression and siRNA knockdown of P58(IPK); Western blot for p-eIF2α, ATF4, Gadd153 The Journal of biological chemistry High 12601012
2006 P58(IPK)/DNAJC3 associates with the ER protein translocation channel Sec61 at the cytosolic face and recruits HSP70 chaperones to that site. P58(IPK) can be crosslinked to nascent proteins entering the ER that are delayed at the translocon. Proteasome-mediated cytosolic degradation of translocating proteins delayed at Sec61 is P58(IPK)-dependent. In P58(IPK)-/- mice, cells with high secretory burden are markedly impaired in coping with ER stress. Co-immunoprecipitation with Sec61; HSP70 recruitment assay; crosslinking of nascent polypeptides; proteasome inhibitor experiments; P58(IPK)-/- mouse model Cell High 16923392
2007 P58(IPK) resides in the ER lumen in association with BiP. ER lumenal P58(IPK) can be co-immunoprecipitated with newly synthesized secretory proteins in vitro and stimulates protein maturation upon overexpression. The stress sensitivity of p58-/- cells is due to impaired protein processing capacity in the ER lumen, not to a defect in the preemptive quality control (pQC) cytosolic pathway or elevated ER substrate burden. Subcellular fractionation; co-immunoprecipitation with BiP and nascent secretory protein; overexpression in cells; stress assays in p58-/- cells; in vitro translation/translocation assay Molecular biology of the cell High 17567950
2006 P58(IPK) regulates influenza virus mRNA translation through a PKR-mediated mechanism independent of PERK. In P58(IPK)-/- mouse embryo fibroblasts, eIF2α phosphorylation increases and influenza virus mRNA translation decreases. Loss of PKR reverses these trends. Loss of PERK has minimal effect on influenza virus mRNA translation despite reduced eIF2α phosphorylation. P58(IPK)-/-, PKR-/-, and PERK-/- mouse embryo fibroblasts; metabolic labeling of viral protein synthesis; eIF2α phosphorylation assays; viral replication assays Journal of virology High 17166899
2005 Deletion of P58(IPK) in mice results in gradual onset of glucosuria, hyperglycemia, and increasing apoptosis of pancreatic islet beta cells. Surviving beta cells are functionally intact, but the loss of P58(IPK) alters expression of apoptosis-associated genes in islets, implicating P58(IPK) as a negative feedback regulator of ER stress-associated apoptosis in secretory cells. P58(IPK)-null mouse generation; glucose and insulin measurements; histopathology; TUNEL apoptosis assay; gene expression arrays in islets Diabetes High 15793246
2010 Crystal structure of the P58(IPK) TPR fragment determined to 2.5 Å resolution reveals three domains (I–III), each containing three TPR motifs. A conserved hydrophobic patch in domain I is required for binding misfolded proteins (luciferase, rhodanese). Structure-based mutagenesis of these hydrophobic residues significantly reduces P58(IPK) molecular chaperone activity. X-ray crystallography (SAD phasing, 2.5 Å); ELISA-based chaperone binding assay with luciferase and rhodanese; structure-based site-directed mutagenesis Journal of molecular biology High 20184891
2011 Crystal structure of human P58(IPK) determined to 3.0 Å resolution shows a highly elongated monomer containing nine N-terminal TPR motifs in three subdomains and a C-terminal J domain attached via a flexible linker. The conserved HPD motif of the J domain is located ~100 Å from the putative misfolded protein-binding site in subdomain I, suggesting that P58(IPK) simultaneously engages substrate and BiP at spatially separated sites. X-ray crystallography (molecular replacement + SAD, 3.0 Å resolution) PloS one High 21799829
2011 P58(IPK) is identified as an interacting partner of the Influenza A virus nucleoprotein (NP)–Hsp40 complex. During IAV infection, expression of NP coincides with dissociation of P58(IPK) from Hsp40 and decreased PKR phosphorylation. Plasmid-based NP expression alone reduces PKR phosphorylation; inhibiting NP expression activates PKR and eIF2α phosphorylation, reduces viral replication, and increases IFN-β production. NP is thus the viral factor activating P58(IPK)-mediated PKR inhibition. Yeast two-hybrid screen; co-immunoprecipitation from mammalian cells; co-localization by immunofluorescence; siRNA knockdown of NP; Western blot for PKR, p-PKR, p-eIF2α PloS one High 21698289
2009 GRP78va, a novel cytosolic isoform of GRP78, interacts with and antagonizes the PERK inhibitor P58(IPK), providing a negative regulatory mechanism on P58(IPK)'s ability to suppress PERK signaling in leukemic cells. siRNA-specific knockdown of GRP78va; co-immunoprecipitation of GRP78va with P58(IPK); PERK signaling assays PloS one Medium 19718440
2010 MK2 and MK3 (MAP kinase-activated protein kinases) interact with p88(rIPK), recruiting a tetrameric complex containing p88(rIPK), P58(IPK), and PKR, resulting in PKR inhibition during influenza A virus infection. Co-immunoprecipitation; MK2/MK3 KO cells and siRNA knockdown; viral replication and PKR phosphorylation assays FASEB journal Medium 20484669
2010 Influenza M2 protein (both A/M2 and BM2) interacts with Hsp40 and with P58(IPK) in vitro and in vivo. Formation of a stable M2–Hsp40–P58(IPK) complex enhances PKR autophosphorylation, in contrast to the inhibitory role of P58(IPK) in the absence of M2, suggesting M2 modulates the Hsp40–P58(IPK)–PKR regulatory axis. Yeast two-hybrid; co-immunoprecipitation; GST pull-down; PKR autophosphorylation assay Protein & cell Medium 21204021
2016 P58(IPK) suppresses NLRP3 inflammasome activation and IL-1β secretion in macrophages through inhibition of PKR. P58(IPK)-deficient macrophages show stronger PKR, NF-κB, and JNK activation; enhanced caspase-1 cleavage; and increased IL-1β maturation. A specific PKR inhibitor or P58(IPK) overexpression abolishes these changes. Co-immunoprecipitation confirmed direct binding of P58(IPK) to PKR but not to other TLR4 downstream signaling molecules. P58(IPK) KO bone marrow-derived macrophages; PKR inhibitor treatment; P58(IPK) overexpression; co-immunoprecipitation; caspase-1 cleavage, IL-1β ELISA Scientific reports High 27113095
2013 P58(IPK) selectively attenuates the PERK–CHOP arm of the UPR during glucose shortage associated with malignant progression, enabling cells to overcome ER stress-induced apoptosis and benefit from chronic UPR protective features. Deletion of CHOP in a K-ras(G12V) lung cancer mouse model increases tumor incidence, confirming ER stress as a barrier to malignancy that p58(IPK) helps overcome. Genetic deletion of CHOP in K-ras(G12V) mouse lung cancer model; p58(IPK) expression manipulation; UPR pathway analysis; glucose flux experiments (hexosamine pathway) Molecular cell High 23395000
2015 In P58(IPK)-/- mice, beta cells develop oxidative stress and apoptosis via ER stress. Deletion of CHOP, treatment with a chemical chaperone, or dietary antioxidant supplementation restores beta-cell function and corrects abnormal MafA localization, placing oxidative stress as an essential proximal signal downstream of P58(IPK) loss required for ER-stress-induced apoptosis. P58(IPK)-/- mice; CHOP deletion rescue; chemical chaperone treatment; antioxidant diet; beta-cell function and mass measurements; MafA immunofluorescence Diabetes High 25795214
2010 Loss of DNAJC3/p58(IPK) (a co-chaperone promoting ATP hydrolysis by BiP) in Sil1-/- mice ameliorates ER stress and neurodegeneration in Purkinje cells, revealing that alterations in the nucleotide exchange cycle of BiP cause ER stress and that reducing ATPase cycling via p58(IPK) loss can rescue neurodegeneration. Genetic epistasis: Sil1-/- crossed with Dnajc3-/- mice; assessment of ER stress markers, ubiquitylated inclusions, and Purkinje cell degeneration Human molecular genetics High 19801575
2016 P58(IPK) specifically co-immunoprecipitates with misfolded (Akita) proinsulin but not with wild-type proinsulin in pancreatic beta cells, indicating P58(IPK) selectively associates with misfolded client proteins in the ER. Co-immunoprecipitation of FLAG-tagged wild-type and Akita proinsulin with endogenous chaperones; mass spectrometry identification; confirmed in two beta cell lines (MIN6 and βTC-6) Biochimica et biophysica acta Medium 26947243
2026 BiP assembles in complexes with the cochaperone p58(IPK) (along with GRP170, ERdj3, PDIA1, PDIA6) that specifically bind nonnative proinsulin. p58(IPK) is required for productive proinsulin folding, as demonstrated by a genetically engineered mouse enabling pulldown of endogenous BiP complexes; nonstoichiometric BiP excess without p58(IPK) hinders proinsulin folding. Endogenous BiP complex pulldown from islet beta cells using genetically engineered mouse; co-immunoprecipitation; proinsulin folding assays with and without p58(IPK) Proceedings of the National Academy of Sciences of the United States of America High 42224595
2013 Synthetic embryonic lethality results from combined deletion of p58(IPK) and ATF6α, demonstrating that the UPR can compensate for genetic impairment of ER protein folding (via p58(IPK)) during normal development, and that p58(IPK) has a required role in embryonic development when ATF6α is absent. Double-KO mouse (Atf6α-/- × p58(IPK)-/-); embryonic viability analysis; tissue histology Biochemical and biophysical research communications Medium 24275136
1996 The human P58(IPK) gene (PRKRI) was mapped by fluorescence in situ hybridization to chromosome 13q32. Fluorescence in situ hybridization (FISH) Genomics Medium 8824808
2009 P58(IPK) promotes the co-translocational degradation pathway for ER-targeted polypeptides with unstructured domains. Overexpression of p58(IPK) promotes co-translocational/preemptive quality control degradation of ER-targeted unstructured polypeptides via the proteasome, particularly targeting N-terminally unstructured domains. Overexpression of p58(IPK) in cells expressing ER-targeted reporter polypeptides with varying secondary structure; proteasome inhibitor assays; translocation efficiency measurements The Journal of biological chemistry Medium 19561072
2024 Dnajc3 modulates axon regeneration in mouse retinal ganglion cells. Knockdown of Dnajc3 in a high-regenerative BXD strain reduces axon regeneration after optic nerve crush, while overexpression of Dnajc3 in a low-regenerative strain increases the number and distance of regenerating axons. Forward genetics in BXD recombinant mouse strains; AAV-mediated overexpression and shRNA knockdown; optic nerve crush model; cholera toxin B axon tracing bioRxivpreprint Low

Source papers

Stage 0 corpus · 76 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Molecular and cellular biology 1752 14559994
2008 UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Developmental cell 490 19081072
2008 Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 365 19109907
2002 Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proceedings of the National Academy of Sciences of the United States of America 316 12446838
2006 Flavivirus infection activates the XBP1 pathway of the unfolded protein response to cope with endoplasmic reticulum stress. Journal of virology 221 16987981
2003 P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. The Journal of biological chemistry 214 12601012
2006 Cotranslocational degradation protects the stressed endoplasmic reticulum from protein overload. Cell 203 16923392
2013 The unfolded protein response and chemical chaperones reduce protein misfolding and colitis in mice. Gastroenterology 200 23336977
2005 Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes 181 15793246
2007 The role of p58IPK in protecting the stressed endoplasmic reticulum. Molecular biology of the cell 176 17567950
2012 Loss of mitofusin 2 promotes endoplasmic reticulum stress. The Journal of biological chemistry 167 22511781
2013 p58(IPK)-mediated attenuation of the proapoptotic PERK-CHOP pathway allows malignant progression upon low glucose. Molecular cell 126 23395000
2009 Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP. PloS one 125 19718440
2013 Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling. Cell metabolism 122 24268736
2006 Reovirus induces and benefits from an integrated cellular stress response. Journal of virology 122 16439558
1999 The cellular inhibitor of the PKR protein kinase, P58(IPK), is an influenza virus-activated co-chaperone that modulates heat shock protein 70 activity. The Journal of biological chemistry 109 9920933
2004 Identification of genes involved in apoptosis and dominant follicle development during follicular waves in cattle. Biology of reproduction 91 14736815
2010 Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjögren syndrome. Human molecular genetics 87 19801575
2011 Involvement of dopamine receptors in binge methamphetamine-induced activation of endoplasmic reticulum and mitochondrial stress pathways. PloS one 84 22174933
2008 Coronavirus infection modulates the unfolded protein response and mediates sustained translational repression. Journal of virology 84 18305036
2010 Coxsackievirus B3 infection activates the unfolded protein response and induces apoptosis through downregulation of p58IPK and activation of CHOP and SREBP1. Journal of virology 83 20554776
2006 The cellular protein P58IPK regulates influenza virus mRNA translation and replication through a PKR-mediated mechanism. Journal of virology 75 17166899
2003 P58(IPK), a plant ortholog of double-stranded RNA-dependent protein kinase PKR inhibitor, functions in viral pathogenesis. Developmental cell 70 12737801
2011 Influenza A virus nucleoprotein exploits Hsp40 to inhibit PKR activation. PloS one 62 21698289
2000 Down-regulation of the endoplasmic reticulum chaperone GRP78/BiP by vomitoxin (Deoxynivalenol). Toxicology and applied pharmacology 51 10652249
2004 Genome-wide analysis of the unfolded protein response in fibroblasts from congenital disorders of glycosylation type-I patients. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 48 15545299
2015 Antioxidants Complement the Requirement for Protein Chaperone Function to Maintain β-Cell Function and Glucose Homeostasis. Diabetes 47 25795214
2013 Tcf19 is a novel islet factor necessary for proliferation and survival in the INS-1 β-cell line. American journal of physiology. Endocrinology and metabolism 42 23860123
2016 Disruption of Protein Processing in the Endoplasmic Reticulum of DYT1 Knock-in Mice Implicates Novel Pathways in Dystonia Pathogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 27707963
2004 Loss of PKR activity in chronic lymphocytic leukemia. International journal of cancer 40 14961569
1996 The 58-kDa cellular inhibitor of the double stranded RNA-dependent protein kinase requires the tetratricopeptide repeat 6 and DnaJ motifs to stimulate protein synthesis in vivo. The Journal of biological chemistry 39 8910500
2009 P58(IPK): a novel "CIHD" member of the host innate defense response against pathogenic virus infection. PLoS pathogens 38 19461876
1999 Inhibition of double-stranded RNA- and tumor necrosis factor alpha-mediated apoptosis by tetratricopeptide repeat protein and cochaperone P58(IPK). Molecular and cellular biology 38 10373525
2016 Mechanism of the induction of endoplasmic reticulum stress by the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT): Activation of PERK/eIF2α, IRE1α, ATF6 and calmodulin kinase. Biochemical pharmacology 36 27059255
2010 Interaction of Hsp40 with influenza virus M2 protein: implications for PKR signaling pathway. Protein & cell 36 21204021
2015 Erp29 Attenuates Cigarette Smoke Extract-Induced Endoplasmic Reticulum Stress and Mitigates Tight Junction Damage in Retinal Pigment Epithelial Cells. Investigative ophthalmology & visual science 35 26431474
2016 A prominent role of PDIA6 in processing of misfolded proinsulin. Biochimica et biophysica acta 34 26947243
2016 p58(IPK) suppresses NLRP3 inflammasome activation and IL-1β production via inhibition of PKR in macrophages. Scientific reports 33 27113095
2015 Inhibition of Brain Mitogen-Activated Protein Kinase Signaling Reduces Central Endoplasmic Reticulum Stress and Inflammation and Sympathetic Nerve Activity in Heart Failure Rats. Hypertension (Dallas, Tex. : 1979) 33 26573710
2011 Heightened induction of proapoptotic signals in response to endoplasmic reticulum stress in primary fibroblasts from a mouse model of longevity. The Journal of biological chemistry 31 21757703
2010 MAP kinase-activated protein kinases 2 and 3 are required for influenza A virus propagation and act via inhibition of PKR. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 31 20484669
2011 ERp29 induces breast cancer cell growth arrest and survival through modulation of activation of p38 and upregulation of ER stress protein p58IPK. Laboratory investigation; a journal of technical methods and pathology 30 22064321
2011 Functional characterization of 58-kilodalton inhibitor of protein kinase in protecting against diabetic retinopathy via the endoplasmic reticulum stress pathway. Molecular vision 29 21245960
2002 Inactivation of the PKR protein kinase and stimulation of mRNA translation by the cellular co-chaperone P58(IPK) does not require J domain function. Biochemistry 27 11939789
2011 Endoplasmic reticulum stress-related factors protect against diabetic retinopathy. Experimental diabetes research 26 22203836
2000 Tissue specific expression of PKR protein kinase in aging B6D2F1 mice. Mechanisms of ageing and development 26 10799709
2015 Identification of p58IPK as a novel neuroprotective factor for retinal neurons. Investigative ophthalmology & visual science 25 25655802
2010 Progressive renal injury from transgenic expression of human carbonic anhydrase IV folding mutants is enhanced by deficiency of p58IPK. Proceedings of the National Academy of Sciences of the United States of America 25 20308551
2017 Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death. Cell death & disease 23 28300830
2009 alpha-Helical domains promote translocation of intrinsically disordered polypeptides into the endoplasmic reticulum. The Journal of biological chemistry 23 19561072
2002 P52rIPK regulates the molecular cochaperone P58IPK to mediate control of the RNA-dependent protein kinase in response to cytoplasmic stress. Biochemistry 23 12269832
2010 Crystal structure of P58(IPK) TPR fragment reveals the mechanism for its molecular chaperone activity in UPR. Journal of molecular biology 22 20184891
2008 P58(IPK) inhibition of endoplasmic reticulum stress in human retinal capillary endothelial cells in vitro. Molecular vision 21 18568130
2015 Cytosolic phospholipase A2α is critical for angiotensin II-induced hypertension and associated cardiovascular pathophysiology. Hypertension (Dallas, Tex. : 1979) 19 25667212
2014 Deletion of P58(IPK), the Cellular Inhibitor of the Protein Kinases PKR and PERK, Causes Bone Changes and Joint Degeneration in Mice. Frontiers in endocrinology 19 25368604
2011 The crystal structure of the human co-chaperone P58(IPK). PloS one 18 21799829
2005 Double-stranded RNA-dependent protein kinase (PKR) is a stress-responsive kinase that induces NFkappaB-mediated resistance against mercury cytotoxicity. Life sciences 18 16324719
2019 The unfolded protein response induced by Tembusu virus infection. BMC veterinary research 17 30670030
2011 Virus infection rapidly activates the P58(IPK) pathway, delaying peak kinase activation to enhance viral replication. Virology 17 21612809
2011 Quinotrierixin inhibited ER stress-induced XBP1 mRNA splicing through inhibition of protein synthesis. Bioscience, biotechnology, and biochemistry 15 21307594
2018 p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells. Frontiers in aging neuroscience 13 30245625
2020 Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group. Pediatric diabetes 11 32738013
2022 Pseudorabies virus infection induces endoplasmic reticulum stress and unfolded protein response in suspension-cultured BHK-21 cells. The Journal of general virology 10 36748498
2020 Porcine circovirus type 2 exploits cap to inhibit PKR activation through interaction with Hsp40. Veterinary microbiology 10 33254057
2018 Deletion of endoplasmic reticulum stress-responsive co-chaperone p58IPK protects mice from diet-induced steatohepatitis. Hepatology research : the official journal of the Japan Society of Hepatology 10 29316085
2013 Synthetic embryonic lethality upon deletion of the ER cochaperone p58(IPK) and the ER stress sensor ATF6α. Biochemical and biophysical research communications 9 24275136
2011 Structural insight into the protective role of P58(IPK) during unfolded protein response. Methods in enzymology 8 21266255
2021 Lutein activates downstream signaling pathways of unfolded protein response in hyperglycemic ARPE-19 cells. European journal of pharmacology 7 34861209
2008 Preliminary X-ray crystallographic studies of mouse UPR responsive protein P58(IPK) TPR fragment. Acta crystallographica. Section F, Structural biology and crystallization communications 7 18259061
1996 Chromosomal assignment of the gene encoding the human 58-kDa inhibitor (PRKRI) of the interferon-induced dsRNA-activated protein kinase to chromosome 13q32. Genomics 7 8824808
2023 Neuronal p58IPK Protects Retinal Ganglion Cells Independently of Macrophage/Microglia Activation in Ocular Hypertension. Cells 6 37371028
2013 P58(IPK) inhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2. Cellular microbiology 6 24134518
2025 Divergent Hepatic and Adipose Tissue Effects of Kupffer Cell Depletion in a Male Rat Model of Metabolic-Associated Steatohepatitis. Biology 4 40906363
2013 Characterization of porcine P58IPK gene and its up-regulation after H1N1 or H3N2 influenza virus infection. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 2 23827789
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2026 Coordinated expression and assembly of BiP, p58IPK, and ER chaperone complexes maximize proinsulin folding in pancreatic β cells. Proceedings of the National Academy of Sciences of the United States of America 0 42224595

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