Inflammation, cellular trafficking, and exosome biogenesis

Inflammatory stimuli and diseases produce a burst of exosome production from affected cells. These exosomes play an important role in cell-cell communication and modulate host responses. These "inflammatory exosomes" have distinct protein and RNA content and are different in both quantity and composition from exosomes produced from the same cells prior to inflammation. Our lab discovered that caspase-1 cleaves a Rab7 adaptor protein called RILP. This cleavage repositions cellular vesicles and leads to an enhancement of plasma membrane fusion events which accounts for the burst of exosome secretion observed during cellular inflammation. Current studies are investigating the molecular details of these interactions, how they determine exosome cargo specificity, and how they can be manipulated to improve the outcome of inflammatory liver disease.

SARS-CoV-2 and host cell interactions

Another ongoing project in the lab investigates the mechanisms by which SARS-CoV-2 modulates cellular trafficking. SARS-CoV-2 is unusual among human viruses for the very high level at which it is shed and the occurrence of super-spreader events which result from a combination of human behavior and unusually high viral shedding. However, the reasons why the virus is able to undergo these rapid transmission events is not understood. Our lab had previously examined the factors that are responsible for efficient shedding of the hepatitis C virus (HCV). We discovered that HCV uses a viral protein called a viroporin to activate a series of events that ultimately causes the cleavage of a cellular protein, RILP, that controls the movement of vesicles within the cell. RILP cleavage severs the linkages that hold newly formed virus particles in the cell and essentially causes them to shoot out of the cell into the environment. Our lab is currently investigating the mechanisms of cellular trafficking modulation by SARS-CoV-2 and examining how manipulating the RILP trafficking axis affects SARS-CoV-2 viral shedding and inflammatory response.

Neuroinflammation and Endocytic Trafficking in Alzheimer’s Disease

'Chronic inflammation is a ubiquitous feature of Alzheimer’s disease and has been proposed to exacerbate the formation of both amyloid plaques and NFTs (neurofibrillary tangles). Another project in our lab investigates how Alzheimer’s disease-induced neuroinflammation alters the endocytic pathway to enhance and promote disease progression. The work lends insight into new druggable targets for Alzheimer disease.

References:

• Ghosh, P., Sasaki, K., Pulido Ruiz, I. A., King, K. E., Weinman, S. A., & Wozniak, A. L. (2023). Inflammatory macrophage to hepatocyte signals can be prevented by extracellular vesicle reprogramming. Journal of cell science, 136(9), jcs260691. https://doi.org/10.1242/jcs.260691
• Wozniak, A. L., Adams, A., King, K. E., Dunn, W., Christenson, L. K., Hung, W. T., & Weinman, S. A. (2020). The RNA binding protein FMR1 controls selective exosomal miRNA cargo loading during inflammation. The Journal of cell biology, 219(10), e201912074. https://doi.org/10.1083/jcb.201912074
• Adams, A., Weinman, S. A., & Wozniak, A. L. (2018). Caspase-1 regulates cellular trafficking via cleavage of the Rab7 adaptor protein RILP. Biochemical and biophysical research communications, 503(4), 2619–2624. https://doi.org/10.1016/j.bbrc.2018.08.013
• Wozniak, A. L., Long, A., Jones-Jamtgaard, K. N., & Weinman, S. A. (2016). Hepatitis C virus promotes virion secretion through cleavage of the Rab7 adaptor protein RILP. Proceedings of the National Academy of Sciences of the United States of America, 113(44), 12484–12489. https://doi.org/10.1073/pnas.1607277113
• Wozniak, A. L., Griffin, S., Rowlands, D., Harris, M., Yi, M., Lemon, S. M., & Weinman, S. A. (2010). Intracellular proton conductance of the hepatitis C virus p7 protein and its contribution to infectious virus production. PLoS pathogens, 6(9), e1001087. https://doi.org/10.1371/journal.ppat.1001087