REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

Abstract

BackgroundHeart failure is a complex syndrome characterized by cardiac contractile impairment with high mortality. Defective intracellular Ca2+ homeostasis is the central cause under this scenario and tightly links to ultrastructural rearrangements of sarcolemmal transverse tubules and the sarcoplasmic reticulum (SR); however, the modulators of the SR architecture remain unknown. The SR has been thought to be a specialized endoplasmic reticulum membrane system. Receptor accessory proteins (REEPs)/DP1/Yop1p are responsible for shaping high‐curvature endoplasmic reticulum tubules. This study aimed to determine the role of REEPs in SR membrane shaping and thus cardiac function.Methods and ResultsWe identified REEP5 (receptor accessory protein 5) as more highly expressed than other REEP members in adult rat ventricular myocardium, and it was downregulated in the failing hearts. Targeted inactivation of REEP5 in rats specially deformed the cardiac SR membrane without affecting transverse tubules, and this was visualized by focused ion beam scanning electron microscopy–based 3‐dimensional reconstruction. Accordingly, simultaneous recordings of depolarization‐induced Ca2+ currents and Ca2+ transients in REEP5‐null cardiomyocytes revealed normal L‐type Ca2+ channel currents but a depressed SR Ca2+ release. Consequently, the excitation–contraction coupling gain of cardiomyocytes and consequent cardiac contractility were compromised. REEP5 deficiency did not alter the expression of major proteins involved in Ca2+ handling in the heart.Conclusions REEP5 modulates cardiac function by shaping the SR. REEP5 defect deforms the SR architecture to depress cardiac contractility. REEP5‐dependent SR shaping might have potential as a therapeutic target for heart failure.

REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects

“…However, given that we observed consistent phenotypes within the myocytes in vitro, and zebrafish and mouse hearts in vivo, it is highly probable that the observed phenotypes are a direct result of REEP5 deficiency. Our results are supported by a recent study that generated CRISPR/Cas9-mediated inactivation of REEP5 in rat ventricular myocardium with a preliminary characterization that showed depressed cardiac contractility in pressure-volume loops 52 . Interestingly, inactivation of REEP5 in rats displayed a weaker and nonlethal cardiac phenotype compared to our REEP5depleted mouse model.…”

<p>Identification of Important Modules and Biomarkers in Breast Cancer Based on WGCNA</p>

“…REEP5 (Receptor accessory protein 5) is a key molecule that maintains the normal function of the cardiac sarcoplasmic reticulum function. 31,32 Chiamvimonvat et al demonstrated that REEP5, as the only REEP family protein enriched in the heart, is a new regulator of cardiac excitation-contraction coupling. 33 Studies have also shown that the expression of REEP5 is down-regulated in lung and gastric cancer.…”

Spastin mutations impair coordination between lipid droplet dispersion and reticulum

“…The convergent functions between Spastin and REEP members are probably crucial for neuronal and muscle tissues. In cardiac muscle from rat, inactivation of REEP5 (OMIM# 125265) induces an alteration of sarcoplasmic reticulum morphology [82], comparable to the effect of Spastin deletion in fish muscle (Fig 3M). Among other Spastin partners, Seipin may represent the main actor to control LD dynamics.…”