GPS2 regulates embryonic angiogenesis by enhancing endothelial cell survival through stabilizing HOIP

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Biology

Background:

• Endothelial cell (EC) death inhibition is vital for angiogenesis.
• HOIP, a key component of LUBAC, is essential for EC survival during embryogenesis, but its stability regulation is unclear.

Purpose of the Study:

• To investigate the role of G protein pathway suppressor 2 (GPS2) in regulating EC survival and embryonic vascularization.
• To elucidate the molecular mechanisms by which GPS2 controls HOIP stability.

Main Methods:

• Generated EC-specific GPS2 deletion mice (Gps2^ECKO).
• Analyzed vascularization defects and embryonic lethality in Gps2^ECKO mice.
• Investigated the interaction between GPS2 and HOIP, and the effect on HOIP ubiquitination and degradation.
• Assessed the impact on TNFR1-mediated cell death and NF-κB activation.

Main Results:

• EC-specific GPS2 deletion caused embryonic lethality at E16.5 due to defective vascularization.
• GPS2 deficiency in ECs led to increased TNFR1-mediated cell death.
• GPS2 binds to HOIP, inhibiting its K48-linked polyubiquitination and preventing proteasomal degradation.
• GPS2 deficiency resulted in HOIP degradation, LUBAC instability, attenuated NF-κB activation, and increased EC death.

Conclusions:

• GPS2 is essential for maintaining vascular integrity during embryogenesis.
• GPS2 stabilizes HOIP, thereby inhibiting TNFR1-mediated endothelial cell death.
• GPS2 regulates EC survival and embryonic vascularization through HOIP stability control.