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bioRxiv · 10.1101/2024.06.03.594717

Distinct Perception Mechanisms of BACH1 Quaternary Structure Degrons by Two F-box Proteins under Oxidative Stress

Cao, S.·Shi, H.·Garcia, S. F.·Kito, Y.·Goldberg, H. V.·Ponce, J.·Ueberheide, B.·Lignitto, L.·Pagano, M.·Zheng, N.
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Abstract

The transcription factor BACH1 regulates heme homeostasis and oxidative stress responses and promotes cancer metastasis upon aberrant accumulation. Its stability is controlled by two F-box protein ubiquitin ligases, FBXO22 and FBXL17. Here we show that the homodimeric BTB domain of BACH1 functions as a previously undescribed quaternary structure degron, which is deciphered by the two F-box proteins via distinct mechanisms. After BACH1 is released from chromatin by heme, FBXO22 asymmetrically recognizes a cross-protomer interface of the intact BACH1 BTB dimer, which is otherwise masked by the co-repressor NCOR1. If the BACH1 BTB dimer escapes the surveillance by FBXO22 due to oxidative modifications, its quaternary structure integrity is probed by a pair of FBXL17, which simultaneously engage and remodel the two BTB protomers into E3-bound monomers for ubiquitination. By unveiling the multifaceted regulatory mechanisms of BACH1 stability, our studies highlight the abilities of ubiquitin ligases to decode high-order protein assemblies and reveal therapeutic opportunities to block cancer invasion via compound-induced BACH1 destabilization.

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Cao, S., Shi, H., Garcia, S. F., Kito, Y., Goldberg, H. V., Ponce, J., Ueberheide, B., Lignitto, L., Pagano, M., Zheng, N.. 2024-06-03. Distinct Perception Mechanisms of BACH1 Quaternary Structure Degrons by Two F-box Proteins under Oxidative Stress. https://doi.org/10.1101/2024.06.03.594717

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