Peroxisome-dependent and -independent functions of PEX19 in mouse embryonic stem cells

Pluripotent embryonic stem cells (ESCs) possess a unique cell cycle pattern to support self-renewal and maintain pluripotency, and remodeling of this cycle by developmental cues is a key priming step for lineage commitment. Here we report an unexpected role of PEX19, a chaperone and receptor for peroxisomal membrane proteins, in regulating cell cycle and cell fates of mouse ESCs (mESCs) through a peroxisome-independent mechanism. We show that deletion of Pex19 in mESCs disrupts peroxisome assembly, elevating reactive oxygen species and impairing peroxisomal lipid metabolism. These peroxisomal defects increase cell death and diminish pluripotency. Intriguingly, PEX19 also interacts with α-tubulin to facilitate assembly of mitotic spindles in mitotic mESCs. Consequently, loss of Pex19 disrupts cell cycle progression and hinders the exit from pluripotency upon induction of neural differentiation, ultimately preventing differentiation of neural stem cells. Our study reveals a non-canonical function of PEX19 and underscores the importance of cell cycle regulation in cell fate decisions.