iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

Abstract

Desmosomes are anchoring junctions that exist in cells that endure physical stress such as cardiac myocytes. The importance of desmosomes in maintaining the homeostasis of the myocardium is underscored by frequent mutations of desmosome components found in human patients and animal models. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a phenotype caused by mutations in desmosomal components in ∼50% of patients, however, the causes in the remaining 50% of patients still remain unknown. A deficiency of inhibitor of apoptosis-stimulating protein of p53 (iASPP), an evolutionarily conserved inhibitor of p53, caused by spontaneous mutation recently has been associated with a lethal autosomal recessive cardiomyopathy in Poll Hereford calves and Wa3 mice. However, the molecular mechanisms that mediate this putative function of iASPP are completely unknown. Here, we show that iASPP is expressed at intercalated discs in human and mouse postmitotic cardiomyocytes. iASPP interacts with desmoplakin and desmin in cardiomyocytes to maintain the integrity of desmosomes and intermediate filament networks in vitro and in vivo. iASPP deficiency specifically induces right ventricular dilatation in mouse embryos at embryonic day 16.5. iASPPdeficient mice with exon 8 deletion (Ppp1r13l Δ8/Δ8 ) die of sudden cardiac death, displaying features of ARVC. Intercalated discs in cardiomyocytes from four of six human ARVC cases show reduced or loss of iASPP. ARVC-derived desmoplakin mutants DSP-1-V30M and DSP-1-S299R exhibit weaker binding to iASPP. These data demonstrate that by interacting with desmoplakin and desmin, iASPP is an important regulator of desmosomal function both in vitro and in vivo. This newly identified property of iASPP may provide new molecular insight into the pathogenesis of ARVC.ARVC | sudden death | desmosome | iASPP | cell-cell junctions

iASPP contributes to cortex rigidity, astral microtubule capture and mitotic spindle positioning

“…Moreover, iASPP did not show the preferential nuclear localization described originally. This is in accordance with previous data showing that iASPP nuclear localization is restricted to specific cell lines, in particular melanoma 24 or undifferentiated epithelial cells 19,33 . In addition our results do not support a model in which iASPP is mostly present in the cytoplasm as an anti-parallel homodimer 24 .…”

“…While earlier studies focused on the ability of iASPP to inhibit p53 16,18 , more recent work has identified new functions of iASPP, associated with the Pro-rich region. For instance, iASPP interacts with desmine and desmoplakin in cardiomyocytes to sustain desmosome integrity 19 and with the Nrf2 transcription factor regulator Keap1, to promote antioxidative signaling 20 . We report here that iASPP interacts with EB1 via a typical SxIP motif located within the intrinsically disordered region.…”

Development of Real-Time Magnetic Resonance Imaging of Mouse Hearts at 9.4 Tesla— Simulations and First Application

“…Furthermore, animal models of cardiovascular disease have to be included in the validation process to establish whether or not the accuracy in normal mice presented extrapolates to pathological cases. The technique should particularly be suitable for mouse models of ventricular arrhythmias [39]. All this will be addressed in future studies.…”

Desmosomal Cadherins

“…Alternatively spliced versions of the Dsc, PKP, and DP proteins have been described. Other proteins that are associated with desmosomes in a tissue-specific manner include Perp, corneodesmosin, envoplakin, periplakin, kasrin, and the newly identified regulator of desmosomes, inhibitor of apoptosis-stimulating protein of p53 (iASPP; Notari et al 2015).…”