EMC-dependent membrane insertion of IER3IP1 sustains efficient ER-to-Golgi trafficking

The endoplasmic reticulum (ER) membrane complex (EMC) acts as an insertase for a distinct subset of membrane proteins, yet how defects in EMC-dependent membrane insertion propagate to downstream secretory pathway function remains poorly understood. Here, we identify Immediate Early Response 3 Interacting Protein 1 (IER3IP1) as an EMC-dependent ER membrane protein whose stable biogenesis is required to sustain efficient ER-to-Golgi trafficking of newly synthesized secretory cargos. Loss of EMC activity destabilizes IER3IP1, resulting in delayed ER export of folding- and trafficking-sensitive proteins, including clusterin and the prion protein, without overt disruption of global ER structure or protein synthesis. We further show that membrane insertion alone is insufficient for IER3IP1 function: a transmembrane domain–dependent intramembrane interaction mediated by the N-terminal segment is required to support cargo export competence. Together, these findings illustrate how defects in membrane protein biogenesis can indirectly constrain secretory pathway output through loss of specific EMC-dependent membrane proteins, establishing a mechanistic link between membrane insertion efficiency, protein stability, and ER export.