HDLBP

HDLBP (Vigilin) is a large, multi-KH-domain RNA-binding protein that functions primarily at the cytoplasmic face of the endoplasmic reticulum, where it binds the majority of ER-localized mRNAs through multivalent recognition of CU-rich coding-sequence motifs and promotes their translation and secretion of the encoded proteins (PMID:35585045). Beyond its central role in ER-associated translation, HDLBP stabilizes specific mRNAs—including GJB2 mRNA and the long noncoding RNA lncFAL—thereby influencing glycolysis, ferroptosis resistance, and immune evasion in cancer contexts (PMID:40343852, PMID:36423520). HDLBP also acts as a protein stabilizer by physically engaging BRAF and RAF1, competing with the E3 ubiquitin ligases ITCH and TRIM71, respectively, to prevent their proteasomal degradation and sustain MAPK signaling, which promotes hepatocellular carcinoma metastasis and sorafenib resistance (PMID:36122630, PMID:36244648). Additionally, HDLBP is a stress granule component that recruits TSC2 to stress granules, linking it to mTOR-related stress responses (PMID:33888601).

1. 1993 High

   Establishing the genomic locus of HDLBP on chromosome 2q37 provided the foundational map position needed for subsequent genetic and functional studies.

   Evidence Somatic cell hybrid analysis and FISH in human cells

   PMID:8390966

   Open questions at the time

   • No functional characterization at this stage
   • No information on protein domain structure or binding partners
2. 1997 Medium

   Detection of HDLBP protein in atherosclerotic plaque cells, with cholesterol-dependent upregulation, suggested an in vivo role in cholesterol metabolism beyond its initial identification as an HDL-binding protein.

   Evidence Immunohistochemistry and in situ hybridization in human atherosclerotic tissue

   PMID:9409201

   Open questions at the time

   • Correlative expression data without loss-of-function evidence
   • Mechanism linking HDLBP to cholesterol handling not defined
3. 2021 Medium

   Identification of TSC2 as a physical binding partner and demonstration that HDLBP recruits TSC2 to stress granules revealed a previously unknown connection between Vigilin and mTOR-related stress signaling.

   Evidence Reciprocal co-immunoprecipitation, immunofluorescence, siRNA knockdown, and mouse tumor model

   PMID:33888601

   Open questions at the time

   • Whether HDLBP's RNA-binding activity is required for SG recruitment of TSC2 is untested
   • Generalizability beyond TSC2-deficient cell models unclear
4. 2022 High

   Comprehensive PAR-CLIP and knockout studies established that HDLBP directly binds >80% of ER-localized mRNAs via CU-rich CDS motifs and is required for their efficient translation and secretion, defining its primary molecular function as an ER-associated translational enhancer.

   Evidence PAR-CLIP, HDLBP-KO cell lines, polysome profiling, secretion assays, proximal proteomics, in vivo xenograft

   PMID:35585045

   Open questions at the time

   • Structural basis of multivalent KH-domain engagement with CU-rich motifs unresolved
   • Whether HDLBP cooperates with SRP for co-translational targeting not directly shown
5. 2022 Medium

   Parallel studies revealed that HDLBP stabilizes oncoproteins BRAF and RAF1 at the protein level by competitively blocking E3 ligases ITCH and TRIM71, respectively, sustaining MAPK signaling and driving HCC metastasis and drug resistance—demonstrating a protein-level chaperone/shielding function distinct from its RNA-binding role.

   Evidence Co-IP/MS identification of BRAF and RAF1 interactions; ubiquitination assays; in vivo HCC models

   PMID:36122630 PMID:36244648

   Open questions at the time

   • Whether RNA binding and protein stabilization functions are structurally separable is unknown
   • Both studies from a single lab; independent replication pending
   • Domain(s) of HDLBP mediating BRAF/RAF1 interaction not mapped
6. 2022 Medium

   Demonstration that HDLBP binds and stabilizes lncFAL, which in turn protects FSP1 from TRIM69-mediated degradation, established an indirect route by which HDLBP suppresses ferroptosis in hepatocellular carcinoma.

   Evidence RIP, RNA pulldown, ubiquitination assays, ferroptosis assays in HCC cells

   PMID:36423520

   Open questions at the time

   • HDLBP's role is indirect (via lncRNA stabilization); whether it binds FSP1 directly is untested
   • Specificity of HDLBP for lncFAL versus other lncRNAs not systematically assessed
7. 2025 Medium

   Identification of GJB2 mRNA as a direct HDLBP target whose stabilization drives glycolysis and CD8+ T-cell exhaustion in lung adenocarcinoma extended the mRNA-stabilizing function to immune evasion in the tumor microenvironment.

   Evidence RIP, gain/loss-of-function, CD8+ T-cell co-culture, in vivo allograft model

   PMID:40343852

   Open questions at the time

   • Binding site on GJB2 mRNA not mapped
   • Whether HDLBP-dependent GJB2 stabilization occurs via the same CU-rich motif mechanism as ER mRNAs is unknown

• Key unresolved questions include the structural basis by which 14–15 KH domains achieve multivalent mRNA engagement, whether HDLBP's RNA-binding and protein-stabilizing functions are mediated by distinct domains and can be genetically separated, and the physiological relevance of HDLBP phosphorylation at S31/S944.
• No high-resolution structure of full-length HDLBP or KH-domain array
• Functional validation of phosphosite roles (S31, S944) lacking
• In vivo genetic models (conditional knockouts) in non-cancer contexts not reported