School of Biomedical Sciences is pleased to invite you to join the following seminar:

Date: 23 May 2023 (Tuesday)
Time: 3:30 pm – 4:30 pm
Venue: Lecture Lecture Theatre 1, G/F, William M.W. Mong Block, 21 Sassoon Road

Speaker: Professor Vivek Malhotra, ICREA Research Professor and Group Leader, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
Talk Title: Mechanism of mucus production

Biography

Professor Malhotra discovered a natural metabolite Ilimaquinone (IQ) that completely vesiculated the flat Golgi cisternae. IQ hyperactivates a fission machinery at the Golgi membranes that, we learnt for the first time, is functionally composed of a trimeric G‐protein, diacylglycerol and protein kinase D. Malhotra showed that cells use the same principle of membrane fission to produce transport carriers for exporting secretory proteins. This was the first demonstration of how vesicles of variable sizes are created without the function of coat proteins. In one of the first genome‐wide analysis in metazoans, Malhotra identified a large number of new genes that were required for transport and Golgi organization. These genes called TANGO include TANGO1, which is essential for assembling an export site at endoplasmic reticulum where it collects and tunnels bulky collagens and other big molecules to the next station of the secretory pathway. Malhotra identified mutations in TANGO1 that lead to collagenopathies thus validating the significance of his discoveries to physiology. Malhotra’s ongoing studies reveal that TANGO1 can be targeted to control tissue scarring and fibrosis. Malhotra showed that TANGO2 is required for fatty acid metabolism, which explain how defects in its function cause rhabdomyolysis, paroxysmal dystonia (https://tango2research.org). Malhotra identified new genes from another genome wide screen that explain how cells control the quantity and quality of mucins secreted and their link to human pathology such as the ulcerative colitis. Malhotra discovered genes that control how proteins, such as antioxidants and cytokines, that cannot enter the conventional ER‐Golgi pathway are secreted.

Abstract
Calcium-induced mucin secretion from goblet cells by exogenous agonist-dependent (stimulated) and -independent (baseline) manner composes the mucus layer that protects our epithelial lining from pathogens and allergens. Hyper and hypo secretion of mucins is linked to several diseases including asthma, chronic obstructive pulmonary disease, Crohn’s disease and colorectal cancer progression. We would like to target mucins to control diseases of airway and colon, but we first need to understand how cells secrete right quantity and quality of mucins under normal physiological conditions.

We performed a genome wide screen to identify Proteins Involved in Mucin Secretion (PIMS) in colon cancer cell lines. Our data reveal that cooperation between the sodium channels TRPM4-TRPM5 and sodium-calcium exchangers (NCXs) promote entry of extracellular Ca++ to release mucin by the stimulated pathway from goblet cells. Baseline mucin secretion, on the other hand, is triggered by intracellular calcium oscillations mostly by the function of ER-located ryanodine receptors (RYRs). These calcium oscillations act via a small Ca++ binding protein KChIP3 to control fusion propensity of mucin granules. KChIP3 bearing mature mucin granules do not fuse to plasma membrane. Upon binding to calcium, KChIP3 dissociates from mature granules, which then fuse to plasma membranes. In other words, KChIP3 attached to the granules acts as a brake- a negative regulator- for fusion of mucin granules to plasma membrane. Loss of KChIP3 results in mucin hypersecretion both in vitro and in vivo (colon of KChIP3-/- mice). KChIP3 thus emerges as a high affinity Ca++ sensor to control baseline mucin secretion.  We have identified a glycosyltransferases FUT8 that controls the viscoelastic properties of mucins. Defects in FUT8 are observed in patients with ulcerative colitis. Another gene TSPAN8 from our collection is helping us address the long standing question of how cells supervise the biphasic release propensity of secretory granules. These findings will be discussed.

ALL ARE WELCOME

Should you have any enquiries, please feel free to contact Miss Angela Wong at 3917 9216.