Vivek Malhotra

Vivek Malhotra received B.Sc. in Biochemistry from Stirling University (Scotland) and D.Phil. in biochemistry from Oxford University. He was a postdoc in the laboratory of James Rothman at Stanford University where he identified the role of NSF in membrane fusion and purified COPI vesicles that transport secretory and retrograde cargoes (1989). He started his independent lab at UC San Diego in 1990, was tenured in 1995 and promoted to full professor in 1999. In 2008, he moved to start and chair the Department of Cell and Developmental Biology at CRG in Barcelona, Spain. As an independent investigator, Malhotra performed the first system wide chemical screen and identified Ilimaquinone (IQ) which converted flat Golgi cisternae to numerous small vesicles, reflecting a key step in protein secretion, i.e., the formation of transport carriers. In another first of its kind, he performed a genome wide screen in metazoan cells, which revealed a number of genes that function in secretion and Golgi membrane organization (TANGO genes). TANGO1 and TALI from this pool of genes are required for the export of bulky cargoes like the collagens and ApoB-lipoproteins, respectively. In another genome-wide screen in cells of the airways and the gut, his lab has identified genes required for mucin secretion that are likely to help understand human pathologies associated with hypo-and hyper secretion of mucins observed in many chronic obstructive pulmonary diseases. Finally, cells secrete a large number of important proteins that by pass the classical ER-Golgi secretory pathway. His lab is the first to identify genes and a new cellular compartment CUPS (Compartment for Unconventional Protein Secretion) involved in this new secretory pathway. Proteins such as Diazepam (Valium) binding inhibitor, SOD1, and insulin degrading enzymes are secreted by this mode and an understanding of their unconventional secretion is therefore of fundamental importance.

Mechanism of collagen secretion

Collagens are the most abundant secretory proteins, comprising 25-30% of the human body weight and essential for skin and tissue organization, and production of mineralized bones. Secreted chylomicrons and VLDL control cholesterol and dietary lipids homeostasis. Clearly these cargoes are extremely important for normal human physiology, but how are these bulky proteins exported if they cannot fit into the known standard transport vesicles of the secretory pathway? Our working model for TANGO1 mediated collagen export is shown schematically.

Steady state. TANGO1(trans membrane protein) bind Sec23/Sec24 (Green) via interaction of its PRD (red) to Sec23 in Sec23/Sec24 complex. This binding is likely weak, which allows Sec13/Sec31 to come on and off Sec23/Sec24. Binding of TANGO1 to collagen (blue trimers) in the ER lumen shifts the equilibrium by increasing binding of TANGO1-PRDs to Sec23.

Stage I-II. Binding to collagen in the lumen increases the avidity of TANGO1 to Sec23. ERGIC 53 containing membranes (light blue) recruited by TANGO1 fuse within the TANGO1 ring and this extra membrane is rapidly consumed into the growing carrier. During this process, TANGO1 can only extend a maximum of 30-50 nm (estimated from the presence of two coiled domains in the cytoplasmic domain of each) perpendicular to the plane of the ER. TANGO1 bound to Sec23/Sec24 therefore remains at the neck of the growing tubule. The growing tip of this tubule, we expect might in fact be coated by both Sec23/Sec24 and Sec13/Sec31, the latter being carried over into the growing tubules from the distribution of the two complexes Sec23/Sec24 described above in the steady state.

Stage III-IV. This growth of the carrier continues till collagen trimers are completely encased in a tubule commensurate with the length of a fully assembled collagen trimer, which in the case of collagen VII might reach greater than 450 nm. Dissociation of collagen releases TANGO1 from Sec23/Sec24 followed by recruitment of Sec13/Sec31 to the neck of the carrier

Separation by membrane fission. The binding of Sec13/Sec31(light yellow) to Sec23/Sec24 initiates Sar1-GTP hydrolysis and membrane fission leading to separation of a collagen filler carrier