Insulin Granule Biogenesis: A New Concept of Protein Sorting in the Golgi Apparatus
I have been deeply fascinated by organelle biology and intracellular protein transport throughout my research career. As a postdoctoral fellow in Vivek Malhotra’s laboratory at the University of California, San Diego, and later at the Center for Genomic Regulation (CRG) in Barcelona, I uncovered a fundamental process by which cells sort and package constitutively secreted proteins. Since the mechanisms governing how these proteins are sorted and packed within the lumen of the Golgi apparatus remain a longstanding mystery in cell biology, I pursued this line of research as an independent group leader at the Max Planck Institute of Biochemistry (MPI-B) in Martinsried, Germany.
At MPI-B, my laboratory combined in vitro reconstitution experiments with cell biology approaches, discovering a molecular sorting mechanism that operates independently of a cargo receptor. Building on this foundation, we have focused on the poorly understood sorting reactions occurring at the trans-Golgi Network (TGN) – particularly how protein and lipid complexes recognize and package secreted proteins into specialized transport carriers.
In 2019, I relocated my laboratory to the Department of Cell Biology at Yale School of Medicine – a department with a rich history in membrane biology founded by George Palade and chaired by James Rothman. I expanded my research at Yale to investigate the mechanisms underlying insulin granule biogenesis in pancreatic beta-cells. We identified chromogranin B as a key driver of insulin granule formation, functioning by generating a condensed protein scaffold within the moderately acidic TGN lumen. This condensate scaffold plays a crucial role in collecting insulin and its processing enzymes, facilitating the budding of immature insulin granules from the TGN.
Given that immune cells, such as neutrophils and mast cells, generate distinct types of granules, our work raises the intriguing possibility that granule-forming factors may also exist in hematopoietic cells, much like chromogranin B functions in insulin-secreting cells. Understanding these mechanisms will shed new light on the molecular basis of protein secretion and pave the way for novel therapeutic approaches for metabolic disorders such as type 2 diabetes, dense-core granule deficiencies, and neurodegenerative disorders.
Date: 14 March 2025, 14:00
Venue: Medical Sciences Teaching Centre, off South Parks Road OX1 3PL
Venue Details: Lecture Theatre
Speaker: Prof Julia von Blume (Yale University, USA)
Organising department: Sir William Dunn School of Pathology
Organiser: Melissa Wright (Sir William Dunn School of Pathology)
Organiser contact email address: melissa.wright@path.ox.ac.uk
Host: Prof Pedro Carvalho (Sir William Dunn School of Pathology)
Part of: Dunn School of Pathology Departmental Seminars
Booking required?: Not required
Audience: Members of the University only
Editor: Melissa Wright