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A20 Promotes Ripoptosome Formation and TNF-Induced Apoptosis via cIAPs Regulation and NIK Stabilization in
Maria Feoktistova1, Roman Makarov1, Sihem Brenji1
1Department of Dermatology and Allergology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.
Cells
|February 8, 2020
Summary
The ubiquitin-editing protein A20 regulates immune responses and is linked to autoimmune disorders. This study reveals A20 promotes TNF-induced cell death in skin cells by stabilizing NIK, impacting inflammatory skin disease treatments.
Area of Science:
- Immunology
- Cell Biology
- Dermatology
Background:
- A20 (TNFAIP3) is a key regulator of immune responses.
- Genome-wide association studies link A20 to inflammatory and autoimmune diseases like psoriasis.
Purpose of the Study:
- To investigate the role of A20 in TNF-induced cell death in keratinocytes.
- To elucidate the molecular mechanisms underlying A20's function in keratinocyte apoptosis.
Main Methods:
- Investigated A20's role in TNF-induced keratinocyte apoptosis.
- Analyzed NF-κB signaling pathways, including noncanonical NF-κB activation.
- Examined the expression and stabilization of key proteins like cIAP1/2, NIK, and TRAF1.
- Studied the formation of the ripoptosome complex.
Main Results:
- A20 acts as a pro-apoptotic factor in TNF-induced keratinocyte cell death.
- A20 modulates cIAP1/2 expression, leading to NIK stabilization and noncanonical NF-κB activation.
- Noncanonical NF-κB signaling upregulates TRAF1, further stabilizing NIK in an autocrine loop.
- Stabilized NIK promotes ripoptosome formation and cell death execution.
Conclusions:
- A20 controls TNF-induced cell death in keratinocytes via multiple regulatory levels.
- This A20-mediated signaling pathway offers potential therapeutic targets for A20-associated skin diseases.
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