Variant-Specific Rewiring of Lysosomal Positioning by STARD9 Produces Opposite Cholesterol Trafficking Outcomes
Year: 2026
Type: preprint
Abstract: Residual cardiovascular risk persists despite lipid-lowering therapy, independent of LDL and Lp(a), reflecting cholesterol dysregulation. We identify STARD9, a lysosomal cholesterol-sensing kinesin, as a causal gene for divergent familial dyslipidemias and premature atherosclerosis. Its START domain binds cholesterol to govern lysosomal positioning. Rare variants segregate with autosomal dominant hypercholesterolemia and premature coronary disease, while common variants associate with reduced HDL and elevated triglycerides. Both converge on lysosomal cholesterol sequestration, ER depletion, mTORC1–SREBP2 activation, impaired autophagy, and NF-κB inflammation, yet diverge through opposite lysosomal positioning: the rare variant disperses lysosomes peripherally, phenocopying START-domain loss across cholesterol sequestration, lysosomal positioning, and TFEB activation, triggering LDLR degradation and CASM/TFEB-dependent efflux that preserves HDL, whereas the common variant causes perinuclear retention that suppresses TFEB-dependent lipid-handling transcripts, yielding hypertriglyceridemia and low HDL. In Stard9-knockout mice, enterocyte cholesterol sequestration drives SREBP2-dependent NPC1L1 upregulation and apical localization, increasing intestinal cholesterol absorption. These findings position lysosomal cholesterol trafficking as a targetable node in statin-refractory cardiovascular disease. Graphical abstract (Left panel) STARD9 mutations p.V2821L and p.I2772V drive divergent cholesterol uptake but converge on a shared lysosomal pathology. While p.V2821L reduces LDL uptake and p.I2772V increases it, both mutations cause lysosomal cholesterol sequestration. This accumulation leads to lysosomal membrane damage and nuclear SREBP2 localization, exacerbating cholesterol dysregulation and cellular stress. Lysosomal damage also disperses lysosomes and activates mTOR, suppressing canonical autophagy while driving NF-κB inflammatory signaling and pro-inflammatory cytokine secretion. (Right panel) Concurrently, lysosomal stress engages CASM specifically in p.V2821L lines, driving paradoxical TFEB activation and increased cholesterol efflux, whereas failure to engage this pathway in p.I2772V lines is associated with reduced TFEB activation and reduced cholesterol efflux.
Institution: Yale University
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214535666