Page 9 - Annual Report 2020

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 Therapeutics
FAPP2-GLTPH domain. Our findings are published
in Nature, PLoS Biology, Structure, The Journal of Biological Chemistry, Biophysical Journal, Biochemistry, and Journal of Lipid Research. The work benefited from collaborations with D.J. Patel, Memorial Sloan Kettering Cancer Center (MSKCC), L. Malinina,
CIC bioGUNE (Derio/Bilbao, Spain) and J.G. Molotkovsky, Shemyakin Institute of Bioogranic Chemistry, Russian Academy of Science.
Recently we discovered new GLTP superfamily members, ceramide-1-phosphate (C1P) transfer proteins (CPTPs). In Nature, we reported structural characterization of human CPTP (D.J. Patel, MSKCC, collaborator), CPTP intracellular location
in mammalian cells (Ted Hinchcliffe, UMN-Hormel Institute, collaborator), and showed that CPTP depletion in human cells by RNAi leads to C1P over-accumulation in the trans-Golgi (Charles Chalfant, Univ. South Florida, collaborator). The C1P over-accumulation triggers cytoplasmic phospho- lipase A2 (cPLA2α) action to generate arachidonic acid and downstream pro inflammatory eicosanoid production. We recently elucidated the selection mechanism used by the cPLA2α C2-domain to target certain phospholipids in eLife. The insights could help develop new treatments for sepsis and other inflammation-associated pathologic condi- tions, i.e. cancer, diabetes and dementia.
In Cell Reports, our X ray structures revealed that ACD11, a plant CPTP, also uses a GLTP-fold evolved to bind and transfer phyto-C1P (D.J. Patel (MSKCC) and John Mundy (Univ. Copenhagen) collaborators). Disruption of acd11 gene impairs plant development by severely altering C1P and ceramide levels to drive programmed cell death. The findings stimulated studies showing that human CPTP functions as
an endogenous regulator of autophagy and inflam- masome assembly that drives interleukin release (IL1B and IL18) reported in Autophagy. In other recent studies in BBA-Cell and Molecular Biology of Lipids, we found that GLTP overexpression induces necroptotic programmed cell death process in certain colon cancer cell types. Our GLTP superfamily discoveries have resulted in invited reviews for Quarterly Reviews of Biophysics, Annual Reviews of Biochemistry, ASBMB TODAY, and Progress in Lipid Research.
Technological advances that simplify and improve methodology for measuring lipid transfer between membrane vesicles have also emerged from our research. As recently published in Analytical Chem- istry, we discovered that uniform-size, stable lipid vesicles form readily by dilution of lipid membrane discs known as bicelles. Included are the first pub-
Figure 2: Cryo-EM of lipid vesicles formed by bicelle dilution
lished images obtained using the Hormel Institute’s new Cryo-Electron Microscope (Amer Alam collaboration). The broad-reaching future potential of our discovery led to filing of a provisional patent by the UMN Technology Commercialization Office.
Our GLTP superfamily protein studies could ultimately facilitate their development as nano- devices for targeted manipulation of cellular sphin- golipid levels that regulate different programmed cell death processes. Such advances could pro- vide new ways to selectively destroy cancer cells and lead to new therapeutic approaches to treat other diseases. The exciting research progress has been fueled by support from NIH National In- stitute of General Medical Sciences, NIH National Heart Lung and Blood Institute, NIH National Can- cer Institute, Southern Minnesota’s Paint-the-Town Pink Initiative, and The Hormel Foundation. More details regarding our research activities, expertise and scientific publications, are available at:
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 research expertise and publications):
https://experts.umn.edu/en/persons/rhoderick-e-brown
Figure 1: CPTP containing bound C1P
THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 9