Essential requirement for IER3IP1 in B cell development

Abstract

In a forward genetic screen of mice withN-ethyl-N-nitrosourea-induced mutations for aberrant immune function, we identified animals with low percentages of B220+cells in the peripheral blood. The causative mutation was inIer3ip1, encoding immediate early response 3 interacting protein 1 (IER3IP1), an endoplasmic reticulum membrane protein mutated in an autosomal recessive neurodevelopmental disorder termed Microcephaly with simplified gyration, Epilepsy and permanent neonatal Diabetes Syndrome (MEDS) in humans. However, no immune function for IER3IP1 had previously been reported. The viable hypomorphicIer3ip1allele uncovered in this study, identical to a reportedIER3IP1variant in a MEDS patient, reveals an essential hematopoietic-intrinsic role for IER3IP1 in B cell development and function. We show that IER3IP1 forms a complex with the Golgi transmembrane protein 167A and limits activation of the unfolded protein response mediated by inositol-requiring enzyme-1α and X-box binding protein 1 in B cells. Our findings suggest that B cell deficiency may be a feature of MEDS.