Powering stem cell decisions with ubiquitin

Many types of pluripotent stem cells exist in a quiescent state within specialized hypoxic niches of the metazoan body. Upon receiving appropriate inputs, these progenitor cells can start to proliferate or commit to differentiation programs that give rise to the different cell types of the developing organism.¹ Stem cells and their derivatives tailor their metabolic program to the demands given by their respective cellular states:² while stem cells rely on anaerobic glycolytic energy production to account for hypoxic conditions in the niche and to minimize production of toxic reactive oxygen species, differentiating cells switch to aerobic metabolism to increase energy production. To achieve this metabolic switch, stem cells regulate the biogenesis and function of mitochondria, the cell’s powerhouses for anaerobic energy production, yet how this process is regulated is not well understood.

The investigators uncovered this pathway by setting out to study the stem cell-specific F-box protein FBXO15, one of ~70 substrate adaptors for SCF (Skp1-Cul1-F-box) ubiquitin E3 ligase complexes. FBXO15 is preferentially expressed in undifferentiated cells, and indeed, had previously been used as a marker for induced pluripotent stem cells.⁴ Through proteomic, biochemical, and genetic analyses, the authors identified KBP as substrate of SCF^FBXO15-mediated proteasomal degradation and determined the molecular basis underlying KBP ubiquitylation. While many F-box proteins recognize their targets following substrate phosphorylation,⁵ FBXO15 relies on prior acetylation of a lysine residue within a conserved degron motif in KBP. Substitution of the critical lysine residue with arginine rendered KBP insensitive to SCF^FBXO15-mediated degradation. Thus, SCF^FBXO15 targets acetylated KBP for proteasomal degradation, rendering FBXO15 one of very few first known acetylation-dependent E3 ligases.

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