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Current research projects:
1) Structural Characterization and Function of Sphingolipid Transfer Proteins in Eukaryotes
2) The Functional Role of the cPLA2α/C1P Interaction in Sepsis Resolution
3) Inflammation in Breast Cancer Initiation and Progression: Intervention Potential by Sphingolipid Transfer Proteins
4) Regulation of Ceramide-1-Phosphate Transfer Protein (CPTP): New Strategy for Enhancing Breast Cancer Therapeutic
Figure 1: Generation of small, homogeneour single-bilayer POPC vesicles by POPC/DHPC bicelle mix dilution
Cell Reports studies of ACD11, a plant CPTP, have revealed a GLTP-fold evolved to bind and transfer phyto-C1P. Disruption of acd11 gene impairs plant development by severely altering C1P and ceramide levels to drive programmed cell death. In an Autophagy
article, we showed that human CPTP functions an endogenous regulator of autophagy and inflammasome assem- bly to drive interleukin release (IL1B and IL18). We also found that GLTP overexpression induces necroptotic programmed cell death in certain colon cancer cell types. Our GLTP superfam- ily discoveries have resulted in invited reviews for Quarterly Reviews of Bio- physics, Annual Reviews of Biochemistry, ASBMB TODAY, and Progress in Lipid Research. Our findings could ultimately facilitate GLTP superfamily protein use as nano-devices for targeted manipula- tion of cellular sphingolipid levels that regulate different programmed cell death processes. Such advances could provide novel therapeutic approaches for selectively destroying cancer cells or treating other diseases.
Our research also has led to techno- logical advances that simplify and improve methodology for in vitro production of membrane vesicles used to measure lipid transfer and protein/ membrane interactions. In Analytical Chemistry, we reported our discovery of uniform-size, stable lipid vesicles read- ily forming upon dilution of lipid mem- brane discs (bicelles). Included are the
first published images utilizing the Hormel Institute’s new Cryo-Electron Microscope. The broad-reaching potential of our discovery led to filing of a patent by the UMN Technology Commercialization Office.
Research Support: NIH (National Institute of General Medical Sciences, National Heart Lung and Blood Institute, National Cancer Institute), Southern Minnesota’s Paint-the-Town Pink Initiative,
The Hormel Foundation.
Collaborators: D.J. Patel, (Memorial Sloan Kettering Cancer Center), Charles Chalfant, (Univ. South Florida), L. Malinina, (CIC bioGUNE, Derio/Bilbao, Spain), J.G. Molotkovsky, (Shemyakin Institute of Bioogranic
Chemistry, Russian Academy of Science),
John Mundy (Univ. Copenhagen), Ted Hinchcliffe and Amer Alam, (UMN-Hormel Institute)
REB Lab research activities:
https://www.hi.umn.edu/portfolio-items/rhoderick- e-brown/
ORCID ID (REB):
https://orcid.org/0000-0002-7337-3604
Experts-UMN (REB):
https://experts.umn.edu/en/persons/rhoderick-e-brown
Figure 2: Ceramide-1-phosphate transfer protein (CPTP) with bound C1P interacting membrane containing PIP2
Publications:
• Gao Y-G, Zhai X, Boldyrev IA, Molotkovsky JG, Patel DJ, Malinina L, Brown RE (2021) Ceramide- 1-phosphate transfer protein (CPTP) regulation by phosphoinositides. J. Biol. Chem. 296:100600.
• Klionsky DJ ...Brown RE....Tong C-K. (2021) Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy 17:1-382.
• Mishra SK, Gao Y-G, Zou X, Stephenson DJ, Malinina L, Hinchcliffe EH, Chalfant CE, Brown RE (2020) Emerging roles for human glycolipid transfer protein superfamily members in the regulation of autophagy, inflammation, and cell death. Prog. Lipid Res. 78:101031.