Bulk RNA seq analysis of hepatocyes isolated from WT and ITPR2 knock-out mice and treated with growth factors.

Proliferation of hepatocytes depends on calcium signals in the nucleoplasm, and we found that these signals depend on the presence of the type 2 inositol trisphosphate receptor (ITPR2) in the nucleus. ITPR2 localized to the nucleus by binding to the nuclear pore protein Nup62, and loss of either one impaired nuclear calcium signaling.

Liver biopsies from patients with the four most common liver diseases showed that ITPR2 and Nup62 were reduced, and the reduction was greatest in patients who had progressed to cirrhosis. Similar results were observed in animal models. These findings define a signaling microdomain in the hepatocyte nucleus that is responsible for nucleoplasmic calcium signals, which becomes progressively disrupted as liver disease progresses.