Adult tissue homeostasis is maintained by residential stem cells. The proliferation and differentiation of adult stem cells must be tightly balanced to avoid excessive proliferation or premature differentiation. However, how stem cell proliferation is properly controlled remains elusive. Here, we find that auxilin (Aux) restricts intestinal stem cell (ISC) proliferation mainly through EGFR signaling. aux depletion leads to excessive ISC proliferation and midgut homeostasis disruption, which is unlikely caused by defective Notch signaling. Aux is expressed in multiple types of intestinal cells. Interestingly, aux depletion causes a dramatic increase in EGFR signaling, with a strong accumulation of EGFR at the plasma membrane and an increased expression of EGFR ligands in response to tissue stress. Furthermore, Aux co-localizes and associates with EGFR. Finally, blocking EGFR signaling completely suppresses the defects caused by aux depletion. Together, these data demonstrate that Aux mainly safeguards EGFR activation to keep a proper ISC proliferation rate to maintain midgut homeostasis.
