The 42 human Kelch-like (KLHL) proteins are critical substrate adapters for E3 ubiquitin ligases and mutations in KLHL genes underlie a range of human diseases, including neurodegeneration and cancer. However, the upstream regulation and downstream effects of most KLHL proteins remain poorly understood.The best-characterized KLHL protein is KEAP1, which binds to the CUL3/RBX1 E3 ligase components to mediate the ubiquitination and destruction of NRF2, a master transcriptional regulator of redox stress signaling. Redox-active compounds disable KEAP1, preventing the ubiquitination of NRF2 by KEAP1/CUL3/RBX1 and allowing NRF2 accumulation and activation. Recently, we reported that KEAP1 is modified by O-linked β-<i>N</i>-acetylglucosamine (O-GlcNAc), a nutrient-sensitive, reversible form of glycosylation, and this modification is required for efficient NRF2 ubiquitination and degradation. Blockade of KEAP1 O-GlcNAcylation by chemical inhibition or nutrient deprivation stabilizes and activates NRF2, revealing a new connection between metabolism and redox stress signaling. Interestingly, we recently discovered that the KLHL protein gigaxonin is also O-GlcNAcylated in a nutrient-dependent manner, and this site-specific glycosylation is required for gigaxonin’s role in proteostasis regulation in human cells. Based on these results, we hypothesize that nutrient-sensitive O-GlcNAcylation of KLHL proteins regulates proteostasis in response to a range of nutrient levels and metabolic stresses. Our results provide new insights into KLHL protein regulation and function and may point to novel therapeutic opportunities in neurodegeneration, cancer and other diseases by manipulating KLHL proteins through O-GlcNAc modulation.

O-GlcNAcylation of KLHL proteins links nutrient sensing to proteostasis

2019 Fall National Meeting

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