HDLBP

HDLBP (Vigilin) is a multivalent RNA-binding protein that couples mRNA fate to protein synthesis and secretion at the endoplasmic reticulum (PMID:35585045). It binds long CU-rich motifs in the coding sequences of the majority of ER-localized mRNAs, and its loss decreases their translation efficiency and impairs protein synthesis and secretion (PMID:35585045); in neurons, HDLBP-dependent transmembrane protein synthesis at the axonal ER feeds back to drive ER exit site formation and supports axon growth and bouton assembly [PMID:bio_10.1101_2025.09.09.674816]. Beyond ER-coupled translation, HDLBP stabilizes specific transcripts in trans, binding and stabilizing GJB2 mRNA to promote glycolysis (PMID:40343852) and binding the lncRNA lncFAL to suppress ferroptosis through competitive inhibition of TRIM69-dependent FSP1 polyubiquitination (PMID:36423520). HDLBP also acts as a protein stabilizer in oncogenic signaling, binding BRAF and RAF1 and shielding them from ubiquitin-proteasome degradation by competing with the E3 ligases ITCH and TRIM71, respectively, thereby sustaining MAPK/EMT signaling (PMID:36122630, PMID:36244648). It additionally associates with the TSC2 tumor suppressor and influences TSC2 recruitment to stress granules (PMID:33888601). The protein was originally identified as a 110-kDa HDL-binding protein encoded at chromosome 2q37 (PMID:8390966).

1. 1993 Medium

   Before molecular characterization, the gene's identity and product were unknown; mapping and biochemical identification established HDLBP as a defined 110-kDa locus, anchoring all subsequent work.

   Evidence Somatic cell hybrid analysis and FISH mapping with biochemical identification of an HDL-binding protein

   PMID:8390966

   Open questions at the time

   • The reported HDL-binding activity is not connected to any later RNA-binding mechanism
   • No domain or functional model established at this stage
2. 2021 Medium

   To understand HDLBP's role in stress responses, its protein partners were probed, showing it associates with TSC2 and influences TSC2 stress granule localization, placing HDLBP in the stress granule compartment.

   Evidence Reciprocal Co-IP, immunofluorescence localization, and knockdown with stress granule quantification

   PMID:33888601

   Open questions at the time

   • Direct binding interface and stoichiometry with TSC2 not defined
   • Functional consequence of TSC2 mislocalization for mTOR signaling not resolved
3. 2022 High

   The central question of how HDLBP controls gene expression was answered by transcriptome-wide mapping showing it binds CU-rich CDS motifs of most ER mRNAs and is required for their efficient translation and secretion, defining HDLBP as an ER-coupled translational regulator.

   Evidence PAR-CLIP, proximity proteomics, and loss-of-function translation/secretion assays in cell lines

   PMID:35585045

   Open questions at the time

   • Mechanism by which CDS binding enhances translation efficiency is not resolved
   • Whether multivalent KH-domain engagement directly recruits the translation machinery is untested
4. 2022 Medium

   Parallel cancer studies revealed a distinct, post-translational role: HDLBP binds BRAF and RAF1 and protects them from degradation by competing with specific E3 ligases, linking HDLBP to MAPK/EMT signaling and therapy resistance.

   Evidence Co-IP with mass spectrometry, ubiquitination assays, and knockdown/overexpression in vitro and in vivo

   PMID:36122630 PMID:36244648

   Open questions at the time

   • Whether HDLBP binds RAF kinases directly or via an adaptor is not established
   • Structural basis for E3 ligase competition unknown
   • Relationship between RNA-binding and protein-stabilizing functions unclear
5. 2022 Medium

   An RNA-based mechanism in redox biology was uncovered: HDLBP binds and stabilizes lncFAL, which competitively blocks TRIM69-dependent FSP1 ubiquitination, establishing HDLBP as a suppressor of ferroptosis.

   Evidence RNA immunoprecipitation, Co-IP, and ferroptosis/FSP1 stability assays in vitro and in vivo

   PMID:36423520

   Open questions at the time

   • Binding determinants on lncFAL not mapped
   • Generality of HDLBP lncRNA stabilization beyond lncFAL untested
6. 2025 Medium

   HDLBP's mRNA-stabilizing activity was extended to immunometabolism, showing it stabilizes GJB2 mRNA to drive glycolysis and CD8+ T cell exhaustion in lung adenocarcinoma.

   Evidence RIP, gain/loss-of-function metabolic readouts, and co-culture and allograft models

   PMID:40343852

   Open questions at the time

   • Sequence motif mediating GJB2 mRNA binding not defined
   • How transcript stabilization mechanistically differs from the CDS-based translational role is unclear
7. 2025 Medium

   The ER-coupled translation role was given a developmental, spatial dimension by showing HDLBP-dependent transmembrane protein synthesis at the axonal ER drives ER exit site formation, establishing a local translation–secretion feedback loop required for axon growth.

   Evidence Live imaging in neurons with genetic loss-of-function and ERES/axon growth phenotyping (preprint)

   PMID:bio_10.1101_2025.09.09.674816

   Open questions at the time

   • Preprint not yet peer-reviewed
   • Molecular link between local translation and ERES biogenesis not defined

• It remains unresolved how HDLBP's multiple activities — ER-coupled CDS-directed translation, cytosolic mRNA/lncRNA stabilization, and protein stabilization via E3 ligase competition — are integrated within a single protein and partitioned across subcellular compartments.
• No structural model linking KH-domain RNA binding to protein-protein stabilization
• Determinants directing HDLBP between ER, cytosol, and stress granules unknown
• No mechanistic account unifying RNA-binding and ubiquitination-competition functions