Ubiquitylation of unphosphorylated c-myc by novel E3 ligase SCFFbxl8

Overexpression of c-myc via increased transcription or decreased protein degradation is common to many cancer etiologies. c-myc protein degradation is mediated by ubiquitin-dependent degradation, and this ubiquitylation is regulated by several E3 ligases. The primary regulator is Fbxw7, which binds to a phospho-degron within c-myc. Here, we identify a new E3 ligase for c-myc, Fbxl8 (F-box and Leucine Rich Repeat Protein 8), as an adaptor component of the SCF (Skp1-Cullin1-F-box protein) ubiquitin ligase complex, for selective c-myc degradation. SCFFbxl8 binds and ubiquitylates c-myc, independent of phosphorylation, revealing that it regulates a pool of c-myc distinct from SCFFbxw7. Loss of Fbxl8 increases c-myc protein levels, protein stability, and cell division, while overexpression of Fbxl8 reduces c-myc protein levels. Concurrent loss of Fbxl8 and Fbxw7 triggers a robust increase in c-myc protein levels consistent with targeting distinct pools of c-myc. This work highlights new mechanisms regulating c-myc degradation.

Automated summary

Overexpression of c-myc is a common feature in many cancer types, and its degradation is mediated by ubiquitin-dependent degradation. Fbxl8, a new E3 ligase, targets c-myc for selective degradation via the SCF ubiquitin ligase complex, independent of the primary regulator Fbxw7. Loss of Fbxl8 increases c-myc protein levels and cell division, while overexpression of Fbxl8 reduces c-myc protein levels.