Ppm1b negatively regulates necroptosis through dephosphorylating Rip3.
Wanze Chen1, Jianfeng Wu1, Lisheng Li1
1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Nature Cell Biology
|March 10, 2015
Summary
Protein phosphatase 1B (Ppm1b) dephosphorylates receptor-interacting protein 3 (Rip3), restricting programmed cell death (necroptosis). Ppm1b deficiency enhances necroptosis, highlighting its inhibitory role.
Area of Science:
- Cellular Biology
- Molecular Biology
- Immunology
Background:
- Receptor-interacting protein 3 (Rip3) auto-phosphorylation is crucial for necroptosis initiation.
- Regulation of Rip3 phosphorylation remains largely uncharacterized.
- Necroptosis is a key form of programmed cell death with implications in disease.
Purpose of the Study:
- To identify regulators of Rip3 phosphorylation.
- To investigate the role of protein phosphatase 1B (Ppm1b) in necroptosis.
- To elucidate the mechanism by which Ppm1b controls necroptosis.
Main Methods:
- Biochemical assays to identify Rip3 phosphatase activity.
- In vitro and in vivo studies using cell cultures and mouse models.
- Analysis of Rip3 phosphorylation status and mixed lineage kinase domain-like protein (Mlkl) recruitment.
Main Results:
- Protein phosphatase 1B (Ppm1b) was identified as a Rip3 phosphatase.
- Ppm1b restricts both spontaneous and TNF-induced necroptosis.
- Ppm1b dephosphorylates Rip3, preventing Mlkl recruitment and subsequent necroptosis.
- Ppm1b deficiency exacerbates TNF-induced necroptosis and tissue damage in mice.
Conclusions:
- Ppm1b acts as a negative regulator of necroptosis.
- Ppm1b selectively suppresses necroptosis by dephosphorylating Rip3.
- Targeting Ppm1b may offer therapeutic strategies for necroptosis-related conditions.
Related Concept Videos
01:16Necrosis
7.4K
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...
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...
7.4K
01:31Regulation of the Unfolded Protein Response
3.2K
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...
3.2K
01:23Negative Regulator Molecules
39.2K
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
39.2K
01:31The Intrinsic Apoptotic Pathway
9.3K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
9.3K
02:27Nonsense-mediated mRNA Decay
12.2K
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
12.2K
01:22PI3K/mTOR/AKT Signaling Pathway
6.5K
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...
6.5K