Our laboratory is interested in understanding the molecular mechanisms responsible for the generation and maintenance of intracellular membrane-bound compartments in the secretory/endocytic pathways of human cells in healthy and disease conditions.
In all eukaryotic cells, intracellular membrane trafficking is critical for essential cellular functions, including protein secretion, post-translational modifications, cell signaling, cell polarization, and cell maintenance. Defects in membrane trafficking can underlie, or exacerbate, many human diseases, including cancer, diabetes mellitus, Alzheimer’s, cystic fibrosis, Hermansky-Pudlak syndrome, and Congenital Disorders of Glycosylation.
Our laboratory has played a principal role in the discovery of novel membrane trafficking factors and published more than 80 original papers in high-profile journals, including Journal of Cell Biology, PNAS, Journal of Neuroscience, Molecular Biology of the Cell, Scientific Reports, Nature Communications, and Nature Optics. Our research has been continuously supported by grants from both NIH and NSF.
We have pioneered the functional analysis of the Conserved Oligomeric Golgi (COG), an evolutionarily conserved protein complex critical for membrane trafficking and protein modifications in the Golgi apparatus. The COG complex interacts with components of the core membrane fusion machinery to orchestrate docking and fusion of transport vesicles with their acceptor membrane. By using state of the art biochemical (in vitro reconstitution), genetic (CRISPR/Cas9 gene editing), and microscopy (superresolution fluorescent, live cell, and electron microscopy) approaches, we are determining how the key components of intracellular membrane trafficking machinery work together to direct efficient protein trafficking in human cells.
The COG complex is manipulated by a variety of viruses (SARS-Cov-2, HIV, Chikungunya, Hepatitis C, Dengue, and Orthopoxvirus), pathogenic bacteria (Chlamydia and Brucella), and toxins (typhoid, SubAB, Shiga, Ricin, and Cholera). Another direction of our work is devoted to understanding how various pathogens are exploiting mammalian intracellular trafficking machinery. It is not clear how these diverse groups of pathogens evolved to rely on COG function. Understanding the molecular basis of COG-pathogen interactions will allow us to develop strategies to protect cells and organisms from pathogen-borne diseases.
Prydz K, Lupashin V, Wang Y, Saraste J. Editorial: Golgi Dynamics in Physiological and Pathological Conditions. Front Cell Dev Biol. doi: 10.3389/fcell.2020.00007 PMCID: PMC7000357
Realegeno, S.; Priyamvada, L.; Kumar, A.; Blackburn, J.B.; Hartloge, C.; Puschnik, A.S.; Sambhara, S.; Olson, V.A.; Carette, J.E.; Lupashin, V.; Satheshkumar, P.S. Conserved Oligomeric Golgi (COG) Complex Proteins Facilitate Orthopoxvirus Entry, Fusion and Spread. Viruses 2020, 12, 707
Blackburn JB, D’Souza Z, Lupashin VV. Maintaining order: COG complex controls Golgi trafficking, processing, and sorting. FEBS Lett. 2019 Aug 5. doi:10.1002/1873-3468.13570. [Epub ahead of print] Review. PubMed PMID: 31381138.
D’Souza Z, Blackburn JB, Kudlyk T, Pokrovskaya ID, Lupashin VV. Defects in COG Mediated Golgi Trafficking Alter Endo-Lysosomal System in Human Cells. Front Cell Dev Biol. 2019 Jul 3;7:118. doi: 10.3389/fcell.2019.00118. eCollection 2019. PubMed PMID: 31334232; PubMed Central PMCID: PMC6616090.
Miller CN, Smith EP, Knodler LA, Cundiff JA, Blackburn JB, Lupashin V, Celli J. A Brucella Type IV effector remodels COG-dependent secretory traffic to promote intracellular replication. Cell Host Microbe. 2017 Sep 13;22(3):317-329.e7.
Comstra SH, Zlatic SA, Gokhale A, Blackburn JB, Werner E, McArthy J, Petris M, D’Souza P, Panuwet P, Boyd Barr D, Lupashin V, Vrailas-Mortimer A, Faundez V. The Interactome of the Copper Transporter ATP7A Belongs to a Network of Neurodevelopmental and Neurodegeneration Factors. ELife 2017 Mar 29;6. pii: e24722. doi: 10.7554/eLife.24722.
Siegel N, Lupashin V, Storrie B, Brooker G. High-magnification super-resolution FINCH microscopy using birefringent crystal lens interferometers. Nature Photonics 2016; 10 (12), 802-808
Willett R, Bailey J, Climer L, Pokrovskaya I, Kudlyk T, Wang W, Lupashin VV. COG lobe B sub-complex engages v-SNARE GS15 and functions via regulated interaction with lobe A sub-complex. Scientific Reports 2016; 6; 29139
Climer LK, Dobretsov M, Lupashin V. Defects in the COG complex and COG-related trafficking regulators affect neuronal Golgi function. Frontiers in Neuroscience 2015; 9, 405.
Willett R, Kudlyk T, Pokrovskaya I, Schonherr R, Ungar D, Duden R, Lupashin VV. COG complexes form spatial landmarks for distinct SNARE complexes. Nature Communications 2013, 4:1553
Richardson BC, Smith RD, Ungar D, Nakamura A, Jeffrey PD, Lupashin VV, Hughson FM. Structural basis for a human glycosylation disorder caused by mutation of the COG4 gene. Proceedings of National Academy of Sciences USA 2009;106(32):13329-13334
Zolov SN, Lupashin VV. Cog3p depletion blocks vesicle-mediated Golgi retrograde trafficking in HeLa cells. Journal of Cell Biology 2005;168(5):747-759.