Junctophilin 2 is a structural protein that connects the transverse tubule membrane to the sarcoplasmic reticulum (SR) membrane in microdomains known as cardiac dyads. A new study published in Science now shows that a cleaved fragment of the junctophilin 2 N-terminus (JP2NT) translocates to the nucleus and has cardioprotective effects through regulation of gene transcription.

Credit: V. Summersby/Springer Nature Limited

The cardiac dyad is the site of Ca2+ entry into cardiomyocytes via voltage-gated L-type Ca2+ channels (LTCCs), which in turn triggers Ca2+-induced Ca2+ release from the SR via the ryanodine receptor 2 (RYR2). Junctophilin 2 is important for establishing and maintaining the 12–15 nm gap between the sarcolemma and SR membranes in the cardiac dyad. Junctophilin 2 cleavage by calpain in response to cardiac stress causes excitation–contraction uncoupling, leading to heart failure progression.

Moreover, the JP2NT fragment generated by junctophilin 2 cleavage has now been shown to have DNA-binding properties. JP2NT translocates to the nucleus, binds to chromatin via an evolutionarily conserved binding domain and competes with the transcription factors MEF2 and TATA-binding protein. As a result, transcription of genes related to cell growth, hypertrophy, inflammation and fibrosis is repressed.

Mice with cardiac-specific overexpression of JP2NT had better cardiac function in response to pressure-overload than control mice. Conversely, mice with a loss-of-function mutation that disables the nuclear translocation of JP2NT had more severe cardiac hypertrophy and worsened heart function in response to pressure-overload than wild-type littermates.

a cleaved fragment of the junctophilin 2 N-terminus … translocates to the nucleus and has cardioprotective effects

“These new findings reveal a previously unknown self-protective mechanism that enables failing cardiomyocytes in the stressed myocardium to transduce mechanical information into salutary transcription reprogramming,” comments Long-Sheng Song, corresponding author of the article. “We plan to use a gene therapy approach to investigate the beneficial effects of delivering JP2NT or functional peptide in preclinical animal models of heart failure.”