Related Experiment Video

Updated: Jun 9, 2025

Tyramide Signal Amplification for the Immunofluorescent Staining of ZBP1-Dependent Phosphorylation of RIPK3 and MLKL After HSV-1 Infection in Human Cells
09:15

Tyramide Signal Amplification for the Immunofluorescent Staining of ZBP1-Dependent Phosphorylation of RIPK3 and MLKL After HSV-1 Infection in Human Cells

Published on: October 20, 2022

2.1K

Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway

Na Zhang1, Jianping Liu2, Rui Guo2

  • 1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 101408, China.

Molecular Cell
|October 29, 2024
PubMed

Insights

S-palmitoylation activates receptor-interacting serine/threonine protein kinase 1 (RIPK1) kinase activity, driving inflammatory diseases when cell death checkpoints fail. This modification, mediated by DHHC5, offers a potential therapeutic target for these conditions.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • Receptor-interacting serine/threonine protein kinase 1 (RIPK1) kinase activity drives inflammatory diseases via apoptosis and necroptosis.
  • Cell death checkpoints normally inhibit RIPK1 kinase activity to prevent detrimental effects.

Purpose of the Study:

  • To elucidate the mechanisms that license RIPK1 kinase activity when cell death checkpoints are disabled.
  • To identify novel modifications and regulators of RIPK1 kinase activity in inflammatory contexts.

Main Methods:

  • Investigated the role of S-palmitoylation in regulating RIPK1 kinase activity using biochemical and cellular assays.
  • Utilized TNF stimulation and cell death checkpoint blockade models.
  • Examined the involvement of DHHC5 and K63-linked ubiquitination in RIPK1 palmitoylation.
  • Analyzed RIPK1 palmitoylation in mouse models of metabolic dysfunction-associated steatohepatitis.

Main Results:

  • Identified S-palmitoylation as a licensing modification for RIPK1 kinase activity.
  • Demonstrated that TNF induces RIPK1 palmitoylation, mediated by DHHC5 and dependent on K63-linked ubiquitination.
  • Showed that palmitoylation enhances RIPK1 kinase activity by promoting kinase domain homo-interaction, leading to cell death upon checkpoint blockade.
  • Found DHHC5 amplification in fatty livers of mice with metabolic dysfunction-associated steatohepatitis, correlating with increased RIPK1 cytotoxicity.

Conclusions:

  • Ubiquitination-dependent palmitoylation licenses RIPK1 kinase activity, driving downstream cell death signaling.
  • RIPK1 palmitoylation is a key mechanism promoting cell death in inflammatory diseases, particularly under conditions of checkpoint failure.
  • RIPK1 palmitoylation represents a potential therapeutic target for treating inflammatory diseases.
Keywords:
DHHC5RIPK1TNF pathwayapoptosismetabolic dysfunction-associated steatohepatitisnecroptosispalmitoyl acyltransferasepalmitoylation

More Related Videos

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

10.8K
Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity07:09

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Published on: January 7, 2019

7.4K

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.4K
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
12.4K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
8.7K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.2K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.7K
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
7.2K