Proinsulin regulators identified with CRISPR screen and in vivo mouse QTL mapping.
Summary
A genome-wide CRISPR screen and mouse QTL mapping converge on Golgi-centered control of proinsulin and identify PDIA6 as a key regulator of proinsulin production. Trafficking toward Golgi increases, and away from Golgi decreases, intracellular proinsulin, independent of proinsulin folding.
Key Findings
- A genome-wide CRISPR screen identified 84 regulators of the intracellular proinsulin/insulin ratio in β-cells.
- Functional annotation pinpointed Golgi trafficking as the primary axis controlling proinsulin storage and levels.
- Mouse QTL mapping converged on PDIA6; PDIA6 knockdown reduced Golgi/secretory granule proinsulin without affecting folding, impairing production via a UPR-independent mechanism.
Clinical Implications
PDIA6 and Golgi-trafficking pathways could be targeted to normalize proinsulin/insulin balance, informing biomarker development and therapeutic strategies for β-cell dysfunction in diabetes.
Why It Matters
This study provides a mechanistic atlas of proinsulin regulation with cross-validation in vivo, nominating PDIA6 and Golgi trafficking as actionable targets for diabetes.
Limitations
- Preclinical models (cell lines and mice) limit direct clinical generalizability.
- Potential context-dependence of trafficking effects across β-cell states and stressors.
Future Directions
Validate PDIA6 and Golgi trafficking targets in human islets ex vivo and in diabetic models in vivo; develop selective modulators and assess impacts on proinsulin/insulin ratio and glycemic control.
Study Information
- Study Type
- Case series
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic research (cell and animal studies), no direct clinical outcomes.
- Study Design
- OTHER