Page 20 - Hormel Report 2023

Rhoderick Brown, PhD
“Unraveling how sphingolipid transfer proteins distribute sphingolipids within cells to help regulate inflammation and cell death is of fundamental importance for developing
new therapeutic approaches to treat diseases
in which normal programmed cell death
processes become altered.”
Rhoderick “Rick” Brown
20 | THE HORMEL INSTITUTE Membrane Biochemistry
PROFESSOR
// UNIVERSITY OF MINNESOTA
Our research focus has centered on proteins that interact transiently with membranes to function. Such proteins
include lipid transfer proteins that shuttle sphin- golipids between intracellular membranes to help form and maintain ‘raft’ microdomains as well as modular lipid-binding protein domains (e.g. C2-domains) that serve as membrane targeting/anchoring devices that enable bigger proteins to function on membranes. Our cloning of glyco(sphingo)lipid transfer proteins (GLTPs) from mammals, plants and fungi enabled X-ray crystallographic resolution of their molecular structures. The unique protein fold (GLTP-fold) revealed a new protein superfamily. We also have deciphered how: i) GLTPs accommodate different glycolipids within its glycolipid binding site; ii) tryptophan functions in glycolipid binding and membrane interaction; iii) the structural basis for altered glycolipid selectivity by fungal GLTP and the human FAPP2-GLTPH domain
as reported in Nature, eLife, PLoS Biology, Structure, JBC, Biophys. J., Biochemistry, and J. Lipid Research.
More recently, we discovered new GLTP superfamily members that bind and transfer ceramide-1-phosphate (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-ac- cumulation triggers cytoplasmic phospholipase A2 (cPLA2α) action that releases arachidonic acid used for downstream pro inflammatory
eicosanoid production. We reported in JBC that including certain phosphoinositides (PIs) to phos- phatidylcholine membranes stimulates CPTP activity and mapped the PI interaction site via point mutation analyses to di-arginine residues in the helix 3-4 connecting loop. We also reported in Autophagy that human CPTP functions to endog- enously regulate autophagy and inflammasome assembly that drives interleukin release (IL1B and IL18). In contrast, GLTP overexpression induces necroptotic cell death in certain colon cancer cell types. The findings could ultimately facilitate use of GLTP superfamily proteins as nano-devices to selectively manipulate cellular sphingolipid levels to enable novel programmed cell death-based therapeutic approaches for selectively destroying cancer cells and treating other diseases. Our GLTP superfamily discoveries have led to invited reviews for Quarterly Rev. Biophysics, Annual Rev. Biochemistry, ASBMB TODAY, and Prog. Lipid Research.