Auxilin in enterocytes controls intestinal homeostasis through inter-cell communication

Residential stem cells sense extrinsic and intrinsic signals to proliferate accordingly to maintain homeostasis. However, how differentiated cells control stem cell proliferation still remains elusive. Here, we find that Auxilin (Aux) maintains enterocyte (EC) integrity to prevent unlimited intestinal stem cell (ISC) proliferation. Depleting aux in ECs leads to excessive ISC proliferation and intestinal homeostasis disruption. Ectopic cytokine production from dying aux-depleted ECs activates JAK/STAT signaling and promotes ISC proliferation. Mechanistically, Aux facilitates anterograde ER-to-Golgi apparatus (GA) vesicle transport by associating with COPII coatomer. Further, the presentation of cell adhesion molecules (CAMs) by ER-to-GA transport is required for intestinal homeostasis. Together, these data demonstrate that Aux maintains EC integrity by mediating ER-to-GA trafficking of CAMs to restrain excessive ISC proliferation. Thus our study uncovers the underlying mechanism of how differentiated cells control stem cell proliferation through inter-cell communication during tissue homeostasis and pathogenesis.