CaMKIIδ Phosphorylates AUP1 to Promote Pancreatic Tissue Repair and Acinar‐to‐Ductal Metaplasia Formation via Mediating PERK‐Dependent Unfolded Protein Responses

ABSTRACT

Pancreatic repair after acute pancreatitis (AP) is essential for restoring tissue integrity, but the intrinsic mechanisms coordinating acinar plasticity and regeneration remain poorly understood. Aberrant Ca ^{2 +} signaling drives acinar injury, but whether Ca ^{2 +} ‐responsive effectors regulate post‐injury repair remains unclear. This study identifies calcium/calmodulin‐dependent protein kinase II δ (CaMKIIδ) as a repair‐associated regulator of pancreatic regeneration. Global Camk2d deletion delays repair after caerulein‐induced AP without altering initial injury severity. Bone marrow chimeras and pancreas‐specific Camk2d deletion further demonstrate that pancreatic, rather than bone marrow‐derived, CaMKIIδ is required for efficient tissue repair. Transcriptomic and ultrastructural analyses reveal that Camk2d deficiency disrupts endoplasmic reticulum (ER) homeostasis and enhances PERK‐dependent unfolded protein response activation. Camk2d ‐deficient pancreas shows impaired acinar‐to‐ductal metaplasia (ADM) programs in vivo and defective ADM formation in ex vivo 3D culture. Integrated proteomic and phosphoproteomic profiling of acinar‐derived ADM identifies ancient ubiquitous protein 1 (AUP1), an ER‐associated degradation regulator, as a previously unrecognized CaMKIIδ‐dependent substrate candidate. Functional analyses show that phosphorylation of the AUP1 S280‐containing serine‐rich region promotes K48‐linked ubiquitination and restrains PERK‐dependent ER stress under pancreatic stress conditions. These findings define a CaMKIIδ–AUP1 axis linking Ca ^{2 +} ‐responsive kinase activity to ER proteostasis, ADM formation and pancreatic repair.