Related Experiment Video

Updated: Jan 17, 2026

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

11.3K

RIPK1 S161 phosphorylation promotes further autophosphorylation and cecal necroptosis in TNF-treated mice

Tao Han1, Chenchen Ruan1, Huiyong Lin1

  • 1State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.

The Journal of Experimental Medicine
|September 25, 2025
PubMed

Insights

Tumor necrosis factor (TNF) signaling is regulated by RIPK1 kinase activity. We found that RIPK1 S161 autophosphorylation is crucial for TNF-induced necroptosis, leading to systemic inflammation and mortality.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Biology

Background:

  • Excessive tumor necrosis factor (TNF) signaling causes systemic inflammatory response syndrome and mortality.
  • Receptor-interacting protein kinase 1 (RIPK1) regulates TNF signaling through kinase-dependent and -independent pathways.

Purpose of the Study:

  • To investigate the role of RIPK1 S161 autophosphorylation in TNF signaling and necroptosis.
  • To elucidate the mechanism by which RIPK1 kinase activity mediates TNF-induced pathology.

Main Methods:

  • Utilized S161 phospho-mimic mutant (S161E) in cells and Ripk1S161E/S161E mice.
  • Administered low-dose TNF to induce necroptosis in vivo.
  • Analyzed necroptosis in intestinal epithelial cells (IECs) and endothelial cells (ECs).
  • Measured IL-6 levels and cecal damage.

Main Results:

  • S161 autophosphorylation is sufficient for RIPK1 kinase-dependent function in vivo.
  • S161E mutation overcomes RIPK1 kinase inhibition, leading to hypersensitivity to TNF.
  • Observed low-dose TNF-induced necroptosis in cecal IECs and ECs.
  • Necroptosis promotes IL-6 production, cecal edema, and mortality.

Conclusions:

  • RIPK1 S161 autophosphorylation is a critical determinant of RIPK1 kinase-dependent TNF signaling.
  • This pathway plays a significant role in TNF-induced cecal pathology and mortality.
  • Targeting RIPK1 kinase activity may offer therapeutic potential in inflammatory diseases.

More Related Videos

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System08:15

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System

Published on: April 11, 2025

851
Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice06:40

Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice

Published on: February 9, 2014

29.1K

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...
5.4K
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...
9.8K
Necrosis01:16

Necrosis

Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
6.3K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.9K
Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and...
4.3K
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...
7.9K