Conserved Regulation of the JAK/STAT Pathway by the Endosomal Protein Asrij Maintains Stem Cell Potency

Asrij/OCIAD1 is an endosomal protein expressed in stem cells and cardiovascular lineages and aberrantly expressed in several cancers. We show that dose-dependent modulation of cytokine-dependent JAK/STAT signaling by Asrij regulates mouse embryonic stem cell pluripotency as well as Drosophila hematopoietic stem cell maintenance. Furthermore, mouse asrij can substitute for Drosophila asrij, indicating that they are true homologs. We identify a conserved region of Asrij that is necessary and sufficient for vesicular localization and function. We also show that Asrij and STAT3 colocalize in endosomes and interact biochemically. We propose that Asrij provides an endosomal scaffold for STAT3 interaction and activation, and may similarly control other circuits that maintain stemness. Thus, Asrij provides a key point of control for spatial and kinetic regulation of stem cell signals. [Display omitted] •Asrij depletion leads to reduced pSTAT level and premature stem cell differentiation•Mouse Asrij interacts with and enhances STAT3 activation to maintain pluripotency•Mouse Asrij can maintain the stem cell state in Drosophila•The OCIA domain is necessary and sufficient for endosomal localization and Asrij function In addition to controlling transport, endosomes can act as scaffolds and create topological constraints to promote specific molecular interactions or generate new, coherent ones. Here, Inamdar and colleagues show that the endosomal protein Asrij interacts with STAT3 and is essential for its activation. Asrij promotes stemness and suppresses differentiation in mouse pluripotent cells and Drosophila hematopoiesis. Through its OCIA domain, Asrij provides a conserved nodal control on stem cells. This knowledge will help improve strategies for stem cell expansion, differentiation, and cell reprogramming.