Identification of a Novel Hypoxia-induced Inflammatory Cell Death Pathway

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Hypoxic tumors resist therapy and promote recurrence.
• RNF213, implicated in Moyamoya disease and immunity, is activated by PTP1B deficiency in hypoxic HER2+ breast cancer.
• PTP1B deficiency promotes cancer cell death via RNF213 activation.

Approach:

• Investigated the reciprocal control of RNF213 phosphorylation by PTP1B and ABL1/2.
• Analyzed RNF213 oligomerization and RZ domain activation upon tyrosine-1275 phosphorylation.
• Examined the ubiquitylation and degradation of CYLD/SPATA2 by RNF213 RZ domain and LUBAC complex.
• Assessed the role of CYLD/SPATA2 degradation in NF-κB activation and pyroptosis.
• Utilized mutagenesis and xenograft models to confirm RNF213's role in PTP1B-dependent tumor cell death.

Key Points:

• PTP1B and ABL1/2 reciprocally regulate RNF213 phosphorylation at Y1275.
• Phosphorylated RNF213 oligomerizes, activating its RZ domain to ubiquitylate and degrade CYLD/SPATA2.
• CYLD/SPATA2 degradation triggers NF-κB activation and hypoxia-induced ER-stress-dependent pyroptosis.
• RNF213's RING domain negatively regulates its RZ domain activity.
• CYLD deletion in xenografts mimics PTP1B deficiency effects; RZ domain is crucial for PTP1B-dependent cell death.

Conclusions:

• Identified a novel PTP1B/RNF213/CYLD/SPATA pathway controlling inflammatory cell death in hypoxic tumors.
• This pathway offers a targetable strategy to eliminate hypoxic tumor cells and potentially
• heat
• cold
• tumors.
• Revealed new insights into RNF213 regulation and its implications for Moyamoya disease, atherosclerosis, and inflammatory/autoimmune disorders.