Evidence for Functional Regulation of the KLHL3/WNK Pathway by O-GlcNAcylation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

The 42-member Kelch-like (KLHL) protein family are adaptors for ubiquitin E3 ligase complexes, governing the stability of a wide range substrates. KLHL proteins critical maintaining proteostasis in variety tissues and mutated human diseases, including cancer, neurodegeneration, familial hyperkalemic hypertension. However, regulation remains incompletely understood. Previously, we reported that two members, KEAP1 gigaxonin, regulated by O-linked β- N -acetylglucosamine (O-GlcNAc), an intracellular form glycosylation. Interestingly, some ubiquitination targets gigaxonin themselves also O-GlcNAcylated, suggesting multi-level control this post-translational modification may influence many pathways. To test hypothesis, examined KLHL3, which ubiquitinates with-no-lysine (WNK) kinases to modulate downstream ion channel activity. Our biochemical glycoproteomic data demonstrate KLHL3 all four WNK (WNK1-4) O-GlcNAcylated. Moreover, our results suggest O-GlcNAcylation affects WNK4 function both osmolarity ferroptosis, with potential implications ranging from blood pressure neuronal health survival. This work demonstrates functional KLHL3/WNK axis supports broader model O-GlcNAc serving as general regulator signaling proteostasis.

Language: Английский

Multi-omics integration reveals YWHAE as a key mediator of ferroptosis in ARDS

Functional & Integrative Genomics, Journal Year: 2025, Volume and Issue: 25(1)

Published: April 22, 2025

Language: Английский