Palmitoylation: policing protein stability and traffic

Abstract: Tumor necrosis factor (TNF)-induced receptor-interacting serine/threonine protein kinase 1 (RIPK1)-mediated cell death, including apoptosis and necroptosis, is increasingly recognized as a major driver of inflammatory diseases. Cell death checkpoints normally suppress RIPK1 kinase to safeguard the organism from its detrimental consequences. However, the mechanisms licensing RIPK1 kinase activity when a protective checkpoint is disabled remain unclear. Here, we identified S-palmitoylation as a licensing modification for RIPK1 kinase. TNF induces RIPK1 palmitoylation, mediated by DHHC5 and dependent on K63-linked ubiquitination of RIPK1, which enhances RIPK1 kinase activity by promoting the homo-interaction of its kinase domain and promotes cell death upon cell death checkpoint blockade. Furthermore, DHHC5 is amplified by fatty acid in the livers of mice with metabolic dysfunction-associated steatohepatitis, contributing to increased RIPK1 cytotoxicity observed in this condition. Our findings reveal that ubiquitination-dependent palmitoylation licenses RIPK1 kinase activity to induce downstream cell death signaling and suggest RIPK1 palmitoylation as a feasible target for inflammatory diseases.

TL;DR: This study reveals that elevated porcupine disrupts lipid metabolism and promotes inflammatory response in metabolic dysfunction-associated steatotic liver disease (MASLD), and pharmacological inhibition of porcupine ameliorates aberrant lipid accumulation and inflammation.

TL;DR: This review aims to summarize the current knowledge of palmitoylation in eukaryotic parasites, highlighting five exemplary mechanisms of parasite virulence dependent on palMIToylation.

TL;DR: relevant information is summarized that illustrates how lipid modification of proteins plays an important role in dictating precise intracellular movements within cells by regulating membrane‐cytosol exchange, through membrane microdomain segregation, or by modifying the flux of the proteins by means of vesicular or diffusional transport systems.

TL;DR: The ubiquitin system plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis as mentioned in this paper.

TL;DR: The emphasis in this review is on the enzymology of prenyl protein processing and the functional significance ofPrenylation in cellular events.

TL;DR: The role of myristate and palmitate in promoting membrane binding as well as specific membrane targeting will be reviewed, with emphasis on the Src family of tyrosine protein kinases and alpha subunits of heterotrimeric G proteins.

TL;DR: It is shown that the specific subcellular distribution of H- and Nras guanosine triphosphate–binding proteins is generated by a constitutive de/reacylation cycle that operates on palmitoylated proteins, driving their rapid exchange between the plasma membrane (PM) and the Golgi apparatus.