CHLSN

CHLSN/C7orf50 encodes Cholesin, a dual-function protein that operates both as a secreted metabolic hormone and as a nuclear nutrient-sensing regulator. As a hormone secreted from the intestine in response to cholesterol absorption, Cholesin binds the orphan GPCR GPR146 and inhibits PKA signaling, suppressing SREBP2-driven hepatic cholesterol synthesis and lowering circulating cholesterol (PMID:38503280). In its intracellular role it localizes to the nucleolus to promote ribosome biogenesis under nutrient-rich conditions and translocates to the nucleoplasm upon nutrient deprivation to augment autophagy, a reversible relocation governed by NAA10-mediated acetylation at lysines 71/72/76 downstream of mTOR (PMID:42139339). This nucleolar function in ribosome assembly is conserved: the yeast ortholog Rbp95 is an RNA-binding protein that contacts helix H95 of 25S rRNA and cooperates with the Npa1 complex during early pre-60S particle maturation (PMID:36018804). C7orf50 also acts as an oncoprotein, promoting hepatocellular carcinoma growth and metastasis by binding AEG-1, driving its nuclear translocation, and activating NF-κB/PAI-1 signaling (PMID:42139339, PMID:41592889).

1. 2022 High

   Before functional assignment in humans, the ancestral role of this protein was unknown; characterizing the yeast ortholog established it as an RNA-binding factor in early ribosome assembly.

   Evidence RNA-binding domain mapping, in vivo UV-crosslinking (CRAC) to 25S rRNA helix H95, Co-IP of pre-60S particles and genetic epistasis with Npa1 complex members in yeast

   PMID:36018804

   Open questions at the time

   • Whether the human protein retains direct RNA binding to rRNA was not tested
   • Structural basis of the H95/Npa1 interaction not resolved
   • Conservation of the two RNA-interacting domains in human CHLSN not established
2. 2024 High

   The physiological function of human CHLSN was undefined; identifying Cholesin as an intestine-secreted hormone established an organ-crosstalk axis controlling systemic cholesterol.

   Evidence Hormone identification, GPR146 receptor binding assays, PKA and SREBP2 pathway readouts, and in vivo mouse models

   PMID:38503280

   Open questions at the time

   • Structure of the Cholesin–GPR146 complex not determined
   • How a nucleolar RNA-binding factor is also secreted as a hormone is unexplained
   • Mechanism linking cholesterol absorption to Cholesin secretion not detailed
3. 2026 High

   It was unknown how the intracellular protein responds to nutrient status; the acetylation-controlled nucleolus-to-nucleoplasm shuttle established it as a switch coupling ribosome biogenesis to autophagy.

   Evidence Subcellular localization imaging/fractionation, site-directed mutagenesis of K71/72/76, mTOR–NAA10 epistasis, in vitro acetyltransferase assay, and in vivo tumor growth assays

   PMID:42139339

   Open questions at the time

   • Direct molecular outputs in autophagy not defined
   • Whether secreted hormone and nuclear pools are functionally connected unclear
   • Deacetylase reversing K71/72/76 not identified
4. 2026 Medium

   The basis of its oncogenic activity was unclear; binding to AEG-1 and activation of NF-κB/PAI-1 established a tumor-promoting signaling mechanism in HCC.

   Evidence Gain/loss-of-function in HCC cell lines, in vivo xenograft and metastasis models, reciprocal Co-IP of C7orf50–AEG-1, nuclear translocation and NF-κB/PAI-1 readouts, macrophage recruitment assays

   PMID:41592889

   Open questions at the time

   • Single-lab Co-IP; binding interface not mapped
   • Relationship between oncogenic AEG-1 binding and the acetylation/nucleolar functions not addressed
   • Direct vs indirect activation of NF-κB/PAI-1 not distinguished

• It remains unresolved how a single protein integrates a secreted cholesterol-regulating hormone function with conserved nucleolar ribosome-biogenesis and nutrient-sensing roles.
• No unified model connecting extracellular hormone and intranuclear functions
• No structural model of the human protein in any of its roles
• Tissue-specific partitioning between secreted and nuclear pools unknown