Essential requirement for IER3IP1 in B cell development

ABSTRACT: In a forward genetic screen of mice with N-ethyl-N-nitrosourea (ENU)-induced mutations for aberrant immune function, we identified animals with low percentages of B220+ cells in the peripheral blood. The causative mutation was in Ier3ip1, 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, IER3IP1 function in immunity remains unknown. The viable hypomorphic Ier3ip1 allele uncovered in this study, identical to a reported IER3IP1 variant in a MEDS patient, reveals an essential hematopoietic-intrinsic role for IER3IP1 in B cell development and function. Cell cycle progression was impaired in Ier3ip1 mutant B cells after polyclonal stimulation. We show evidence that IER3IP1 forms a complex with the Golgi membrane protein TMEM167A and limits aberrant activation of the unfolded protein response mediated by IRE1 and XBP1 in B cells. Our findings suggest that B immunodeficiency may be a previously unrecognized feature of MEDS.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jin Huk Choi  

PROVIDER: MSV000091025 | MassIVE | Mon Jan 09 12:02:00 GMT 2023

REPOSITORIES: MassIVE