KDELR2

KDELR2 is a seven-transmembrane receptor at the cis-Golgi that retrieves escaped ER-resident chaperones bearing KDEL motifs via COPI-dependent retrograde transport, thereby maintaining ER proteostasis and governing Golgi organization. Overexpression of KDELR2 redistributes β-COP to the cytosol and collapses Golgi structure into the ER, blocking anterograde traffic (PMID:1316805), while its loss prevents retrograde recycling of the collagen chaperone HSP47, causing HSP47 to persist on extracellular collagen fibrils and disrupt fibrillogenesis, resulting in osteogenesis imperfecta (PMID:33053334). KDELR2 also retains ER chaperones calnexin and GRP78/BiP, limiting their availability for viral glycoprotein folding (PMID:30621148), and its depletion activates ER stress effectors CHOP, JNK, and p38 leading to apoptosis (PMID:35116653). Beyond ER quality control, KDELR2 enhances Golgi-mediated MMP secretion to promote cancer cell invasion (PMID:32753652) and is transcriptionally regulated by HDAC3/CREB1 and HIF1α (PMID:34146461, PMID:31342232).

1. 1992 High

   It was unknown whether additional KDEL receptors existed or how they influenced Golgi-to-ER traffic; overexpression of the novel KDELR2 (ELP-1) showed it could redistribute β-COP and collapse the Golgi into the ER, establishing KDELR2 as a bona fide retrograde trafficking regulator.

   Evidence Overexpression in multiple cell types with immunofluorescence, subcellular fractionation, and glycosylation assays

   PMID:1316805

   Open questions at the time

   • Endogenous cargo specificity of KDELR2 versus KDELR1 was not resolved
   • Structural basis of KDEL peptide recognition by KDELR2 was unknown
   • Physiological consequence of KDELR2 loss of function was not tested
2. 2019 Medium

   It was unclear what regulated KDELR2 expression; ChIP-qPCR and luciferase assays showed HIF1α directly binds the KDELR2 promoter, and separately, overexpression/silencing experiments demonstrated KDELR2 retains ER chaperones calnexin and GRP78, limiting their availability for measles virus glycoprotein folding.

   Evidence ChIP-qPCR and luciferase reporter (glioblastoma cells); co-immunoprecipitation and viral titer assays (Vero and T cells)

   PMID:30621148 PMID:31342232

   Open questions at the time

   • Whether HIF1α-driven KDELR2 upregulation is sufficient to alter ER proteostasis in hypoxia was not tested
   • Direct binding of KDELR2 to calnexin or GRP78 KDEL motifs was not demonstrated biochemically
3. 2020 High

   The physiological consequence of KDELR2 loss was unknown; patient-derived loss-of-function KDELR2 variants were shown to prevent HSP47 retrograde retrieval, causing extracellular HSP47-collagen retention and defective fibrillogenesis, establishing KDELR2 mutations as a cause of osteogenesis imperfecta.

   Evidence Patient fibroblast analysis, crystal structure mapping of OI variants onto KDELR2 structure, co-immunoprecipitation, collagen secretion assays

   PMID:33053334

   Open questions at the time

   • Whether KDELR1 or KDELR3 can partially compensate for KDELR2 in HSP47 retrieval was not resolved
   • Full atomic structure of human KDELR2 bound to HSP47 KDEL peptide was not determined
4. 2020 Medium

   Whether KDELR2 influenced secretory cargo beyond ER-resident proteins was unknown; a gain-of-function invasion screen identified KDELR2 as a driver of lung cancer metastasis through enhanced Golgi-mediated MMP secretion, establishing a pro-invasive function.

   Evidence Unbiased invasion screen, in vitro and in vivo metastasis assays, MMP inhibitor rescue

   PMID:32753652

   Open questions at the time

   • The mechanism by which KDELR2 enhances anterograde MMP secretion from the Golgi was not defined
   • Whether this reflects altered COPI vesicle dynamics or a separate signaling function was not distinguished
5. 2021 Medium

   How KDELR2 expression is controlled and whether it has non-canonical functions beyond cargo retrieval was unresolved; HDAC3/CREB1 was shown to transcriptionally activate KDELR2, and KDELR2 was found to protect the centrosomal protein POC5 from proteasomal degradation, accelerating cell cycle progression.

   Evidence ChIP assay (CREB1-KDELR2 promoter), co-immunoprecipitation (KDELR2–POC5), cell cycle analysis, in vivo breast cancer model

   PMID:34146461

   Open questions at the time

   • How a Golgi-localized receptor protects a centrosomal protein from degradation is mechanistically unexplained
   • Whether KDELR2-POC5 interaction is direct or mediated through an adaptor was not established
6. 2021 Medium

   Whether KDELR2 depletion triggers ER stress was unknown; knockdown activated CHOP, phospho-JNK, and phospho-p38, leading to apoptosis that synergized with temozolomide in glioma cells, linking KDELR2 to ER stress suppression.

   Evidence siRNA knockdown, Western blot for multiple UPR and MAPK markers, flow cytometry for apoptosis

   PMID:35116653

   Open questions at the time

   • Whether ER stress results from general chaperone mislocalization or a specific KDELR2-dependent signal was not resolved
   • Synergy with temozolomide was shown only in one glioma cell line
7. 2024 Low

   Broader physiological roles of KDELR2 outside cancer remained unclear; KDELR2 was shown to promote osteogenic differentiation via GSK3β/β-catenin activation and to be required for MUC5AC hypersecretion in COPD airways downstream of ATF6 and IRE1α/XBP-1s.

   Evidence Overexpression/knockdown in mesenchymal stem cells and fracture model; siRNA and IRE1α inhibitor in COPD rat model

   PMID:38470494 PMID:39365189

   Open questions at the time

   • GSK3β/β-catenin activation by KDELR2 is correlative; direct mechanistic link is not established
   • Whether KDELR2 role in MUC5AC secretion reflects canonical retrieval function or a distinct secretory pathway remains unknown
   • Both findings are from single laboratories without independent replication

• It remains unknown how KDELR2's canonical retrograde retrieval activity relates to its reported non-canonical roles in MMP secretion, centrosomal protein stabilization, and Wnt signaling — specifically whether these functions reflect a unified COPI-dependent mechanism, Golgi-localized signaling, or independent activities.
• No structural model of human KDELR2 with bound KDEL peptide exists
• Functional redundancy among KDELR1, KDELR2, and KDELR3 is poorly characterized
• The mechanism coupling KDELR2 to anterograde secretory cargo (MMPs, MUC5AC) is undefined