Throughout life, cells communicate to coordinate the organism’s response to stimuli. Cells release extracellular vesicles that carry signals to alter development or disease response. Released vesicles can also seal the cell membrane after damage. The goal of our research is to discover how vesicles bud from the surface of cells, how cells take up extracellular vesicles, and what signals extracellular vesicles send in animals. Defining how vesicles form is an essential first step to designing strategies to induce or suppress their formation and thereby determine their signaling capability. This research could also lead to new strategies to monitor or influence disease severity.
Most cells release extracellular vesicles (EVs) carrying lipid, protein, and nucleic acid signals. While much is known about their signaling potential, EV formation is poorly understood. As a postdoctoral fellow, Dr. Wehman used the genetic model system C. elegans to discover the first protein that prevents EV budding, TAT-5. In tat-5 mutant worms, too many EVs are produced. TAT-5 is an evolutionarily conserved protein that regulates the distribution of specific lipids across the two layers of the plasma membrane. This finding suggests that lipids have instructive roles in regulating membrane dynamics. Our research aims to define exactly how TAT-5 and lipid distribution regulate EV budding.
In addition to TAT-5, conserved regulators of viral budding also have a role in EV budding in C. elegans, including the small GTPase RAB-11 and the membrane-sculpting complex known as ESCRT. Using the same strategy that identified TAT-5, RAB-11, and the ESCRT machinery, we are using the power of C. elegans genetics to identify additional proteins that regulate EV budding. Our studies are building a pathway of proteins that regulate TAT-5 localization and activity and thereby EV release. The proteins we identify may be used to alter EV production in other systems, which could impact the availability of non-invasive biomarkers and have the potential to influence disease state.
In addition to overproducing EVs, tat-5 mutant worms also have defects in EV uptake. Studying tat-5 and other mutants revealed that cells take up organelles released during cell division, including the mitotic midbody and the meiotic polar body. Thus, we can also use C. elegans to study the pathways of EV uptake and determine their fate. Analyzing defects in EV uptake complements our studies on EV budding and will allow us to elucidate the interplay of lipids and lipid regulators during dynamic remodeling of the membrane. Studying the fate of EVs also provides important insights into the mechanisms of EV signaling.
Finally, studying the mechanisms of EV production has provided us with techniques to induce or prevent their formation. This allows us to test which signaling pathways require EVs for signaling to occur. In flies and mice, EVs carry morphogens important for development. We are studying how changing EV production or uptake affects conserved signaling pathways during C. elegans development. In summary, our research will determine the roles of lipid and protein molecules during membrane dynamics and will define the intercellular signaling roles of EVs.
22 May 2018
University of Washington student Alida Melse has joined the lab for a summer project researching the intracellular trafficking of TAT-5 protein. Alida received a scholarship from the DAAD RISE program.
16 May 2018
Graduate student Gholamreza Fazeli and our team members Maurice Stetter and Jaime N. Lisack published an article in the Cell Reports journal. His study shows how embryos dispose of the life-threatening leftovers of egg maturation. Link to the Press Release.
30 Sep 2016
Graduate student Katharina Beer’s review about the developmental and behavioral roles of extracellular vesicles in flies and worms has been published in Cell Adhesion & Migration. The review also discusses the molecular mechanisms of extracellular vesicle formation. Link to the publication
26 Sep 2016
Recent Ithaca College graduate Jaime Lisack has joined the lab. She was awarded a Fulbright scholarship to study the fate of the polar body.
25 Aug 2016
Postdoc Ahmad Fazeli's work with medical students Michaela Trinkwalder and Linda Irmisch on the post-mitotic fate of the midbody has been published in J Cell Sci. They discovered that autophagy proteins are used for phagosome maturation during midbody degradation, not for macroautophagy. Link to the publication
9 May 2016
Graduate student Katharina Beer was invited to give a talk during a special plenary session of the International Society for Extracellular Vesicles (ISEV) meeting in May in Rotterdam. She received the "Outstanding Abstract Award" for her work on the role of PAD-1 in extracellular vesicle formation.
7 March 2016
Bachelor student Sarah Tröger presented a talk on her internship defining the differences between autophagy and LC3-associated phagocytosis (LAP) at the Würzburg Worm Club. The next meeting will be May 2nd.
29 Sep 2015
The Wehman lab traveled to the Stuttgart Zoo and Botanical Garden for their annual lab excursion.
Gholamreza Fazeli, Maurice Stetter, Jaime N. Lisack und Ann M. Wehman (2018):C. elegans blastomeres clear the corpse of the second polar body by LC3-associated phagocytosis; Cell Report; DOI: 10.1016/j.celrep.2018.04.043
Beer, K.B., Rivas-Castillo, J., Kuhn, K., Fazeli, G., Karmann, B., Nance, J.F., Stigloher, C. and Wehman A.M. (2018) Extracellular vesicle budding is inhibited by redundant regulators of TAT-5 flippase localization and phospholipid asymmetry. PNAS. DOI:10.1073/pnas.1714085115
Fazeli, G., Wehman, A.M. (2017). Safely removing cell debris with LC3-associated phagocytosis.Biol Cell. DOI: 10.1111/boc.201700028
Fazeli, G., Wehman, A.M. (2017). Rab GTPases mature the LC3-associated midbody phagosome.Comm Int Biol 10(2): e1297349. DOI: 10.1080/19420889.2017.1297349
Beer, K.B., Wehman A.M. (2017) Mechanisms and functions of extracellular vesicle release in vivo - What we can learn from flies and worms. Cell Adh Migr 11(2):135-150. Review
Fazeli, G., Trinkwalder, M., Irmisch, L., Wehman, A.M. (2016). C. elegans midbodies are released, phagocytosed, and undergo LC3-dependent degradation independent of macroautophagy. J Cell Sci 129(20):3721-3731
Wehman, A.M., Poggioli, C., Schweinsberg, P., Grant, B.D., Nance, J. (2011). The phospholipid flippase TAT-5 inhibits the budding of extracellular vesicles in C. elegans embryos. Curr Biol 21(23):1951-1959.
Dr. Gholamreza Fazeli
Junior Group Leader at the Rudolf Virchow Center of the University of Würzburg (since January 2013)
|06/2006-12/2012||Postdoctoral Fellow at the Skirball Institute, NYU Medical Center with Jeremy Nance|
|09/1999-03/2006||Ph.D., Genetics & Developmental Biology at University of California, San Francisco (UCSF)|
Fellowships and Awards
American Cancer Society Postdoctoral Fellowship (2008-2011)
Member- Graduate School of Life Siences
Supervisor - Biomedicine
The current term program can be found here.