RETREG1‐Mediated Reticulophagy is Essential for Dendritic Cell Maturation and Function in Sepsis

ABSTRACT Dendritic cells (DCs) are crucial antigen‐presenting cells that mediate the interplay between innate and adaptive immunity during lethal infections. Here, we report the key role of reticulophagy regulator 1 (RETREG1), a selective autophagy receptor, in maintaining DC maturation and function in the early stage of sepsis. Mechanistically, activating transcription factor 6 (ATF6) acts as a direct transcription factor regulating RETREG1 expression in response to bacterial lipopolysaccharide‐induced endoplasmic reticulum (ER) stress. RETREG1‐mediated reticulophagy reduces excessive ER stress via the eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) signaling pathway and inhibits membrane‐associated RING‐CH‐type finger 8 (MARCH8)‐dependent major histocompatibility complex class II (MHC‐II) ubiquitination to maintain antigen presentation in DCs. Consequently, Cd11c cre Retreg1 fl/fl , Retreg1 −/− , and Atf6 −/− mice exhibit impaired DC function, leading to immunosuppression and multiple organ failure in experimental sepsis. Exploration of samples from septic patients, combined with single‐cell bioinformatics analysis, further suggests that a deficit in reticulophagy in DCs is associated with the development of human sepsis.