Regulation of Death Receptor Signaling by S-Palmitoylation and Detergent-Resistant Membrane Micro Domains—Greasing the Gears of Extrinsic Cell Death Induction, Survival, and Inflammation

SIMPLE SUMMARY: Death receptor activation can induce various signaling cascades ranging from cell survival to different forms of regulated cell death. The diversification of these biological outcomes frequently depends on the subcellular localization of the receptors. Activation by their ligands at the plasma membrane can change their plasma membrane localization to form distinct receptor–ligand bound signaling complexes. Receptors can also be internalized to signal from endosomes or the nuclear compartment. Those signaling complexes can be further remodeled en route and are partially released to signal from the cytoplasm. Reversible post-translational modification via S-Palmitoylation, a form of lipidation, emanated as a major regulator of death receptor signaling over the past years. We highlight what is known about S-Palmitoylation in different receptor systems, how it affects localization of the receptor complexes in specialized membrane micro domains, and the functional consequences and therapeutical potential of altered S-palmitoylation in the respective signaling cascades. ABSTRACT: Death-receptor-mediated signaling results in either cell death or survival. Such opposite signaling cascades emanate from receptor-associated signaling complexes, which are often formed in different subcellular locations. The proteins involved are frequently post-translationally modified (PTM) by ubiquitination, phosphorylation, or glycosylation to allow proper spatio-temporal regulation/recruitment of these signaling complexes in a defined cellular compartment. During the last couple of years, increasing attention has been paid to the reversible cysteine-centered PTM S-palmitoylation. This PTM regulates the hydrophobicity of soluble and membrane proteins and modulates protein:protein interaction and their interaction with distinct membrane micro-domains (i.e., lipid rafts). We conclude with which functional and mechanistic roles for S-palmitoylation as well as different forms of membrane micro-domains in death-receptor-mediated signal transduction were unraveled in the last two decades.