Page 18 - Hormel Institute Annual Report 2021-22

Rhoderick Brown, PhD
“Unraveling how sphingolipid transfer proteins help regulate inflammation and cell death is of fundamental importance for developing new therapeutic approaches to treat diseases such as cancer that often develop chemoresis- tance to evade normal programmed cell
death processes.”
Rhoderick “Rick” Brown
18 | THE HORMEL INSTITUTE Membrane Biochemistry
PROFESSOR
// UNIVERSITY OF MINNESOTA
Our research focuses on proteins that interact transiently with membranes to function. Such proteins include lipid
transfer proteins that shuttle sphingolipids between intracellular membranes to help form and maintain ‘raft’ microdomains. Modular lipid-binding protein domains (e.g. C2-domains) also act as membrane targeting and anchoring devices for bigger proteins that need to migrate to membranes to function. Glyco(sphingo)lipid transfer protein (GLTP) cloning from mammals, plants and fungi by us enabled determination
of their molecular structures by X ray crystal- lography. A unique protein fold (GLTP-fold) was discovered. We also deciphered how: i) GLTP accommodates different glycolipids within its glycolipid binding site; ii) the function played by tryptophans in glycolipid binding and membrane interaction; iii) the structural basis for more focused glycolipid selectivity by fungal GLTP
and the human FAPP2-GLTPH domain. Our findings are reported in Nature, eLife, PLoS Biology, Structure, The Journal of Biological Chemistry,
Biophysical Journal, Biochemistry, and Journal of Lipid Research.
We subsequently discovered new GLTP superfamily members that
bind and transfer ceramide-1-phos- phate (C1P), i.e. CPTPs. In Nature, we reported structural characterization of human CPTP, its intracellular location in mammalian cells, and showed that CPTP depletion by RNAi leads to C1P over-accumulation in the trans-Golgi. The C1P over-accumulation triggers cytoplasmic phospholipase A2
(cPLA2α) action that releases arachidonic
acid used for downstream pro inflammatory eicosanoid production. We recently reported in the Journal of Biological Chemistry that adding phosphatidylserine or certain phosphoinositides to PC membranes can stimulate CPTP activity. The precise location of the phosphoinositide interaction site was mapped via point mutation analyses to di-arginine residues in the helix 3-4 connecting loop. We also have recently reported in Autophagy that human CPTP functions as
an endogenous regulator of autophagy and inflammasome assembly that drives interleukin release (IL1B and IL18). In contrast, GLTP over- expression can induce necroptotic programmed cell death in certain colon cancer cell types. Our GLTP superfamily discoveries have resulted in invited reviews for Quarterly Reviews of Biophys-