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Adenovirus targets transcriptional and posttranslational mechanisms to limit gap junction function.

腺病毒靶向转录和翻译后机制限制缝隙连接功能。

  • 影响因子:4.32
  • DOI:10.1096/fj.202000667R
  • 作者列表:"Calhoun PJ","Phan AV","Taylor JD","James CC","Padget RL","Zeitz MJ","Smyth JW
  • 发表时间:2020-06-02
Abstract

:Adenoviruses are responsible for a spectrum of pathogenesis including viral myocarditis. The gap junction protein connexin43 (Cx43, gene name GJA1) facilitates rapid propagation of action potentials necessary for each heartbeat. Gap junctions also propagate innate and adaptive antiviral immune responses, but how viruses may target these structures is not understood. Given this immunological role of Cx43, we hypothesized that gap junctions would be targeted during adenovirus type 5 (Ad5) infection. We find reduced Cx43 protein levels due to decreased GJA1 mRNA transcripts dependent upon β-catenin transcriptional activity during Ad5 infection, with early viral protein E4orf1 sufficient to induce β-catenin phosphorylation. Loss of gap junction function occurs prior to reduced Cx43 protein levels with Ad5 infection rapidly inducing Cx43 phosphorylation events consistent with altered gap junction conductance. Direct Cx43 interaction with ZO-1 plays a critical role in gap junction regulation. We find loss of Cx43/ZO-1 complexing during Ad5 infection by co-immunoprecipitation and complementary studies in human induced pluripotent stem cell derived-cardiomyocytes reveal Cx43 gap junction remodeling by reduced ZO-1 complexing. These findings reveal specific targeting of gap junction function by Ad5 leading to loss of intercellular communication which would contribute to dangerous pathological states including arrhythmias in infected hearts.

摘要

腺病毒负责包括病毒性心肌炎在内的一系列发病机制。缝隙连接蛋白 43 (Cx43,基因名 GJA1) 有利于每次心跳所需动作电位的快速传播。缝隙连接也传播固有和适应性抗病毒免疫反应,但病毒如何靶向这些结构尚不清楚。鉴于 Cx43 的这种免疫学作用,我们假设缝隙连接在腺病毒 5 型 (Ad5) 感染过程中会被靶向。我们发现 Cx43 蛋白水平降低是由于在 Ad5 感染过程中依赖于 β-catenin 转录活性的 GJA1 mRNA 转录减少,早期病毒蛋白 E4orf1 足以诱导 β-catenin 磷酸化。在 Ad5 感染快速诱导 Cx43 磷酸化事件与缝隙连接电导改变一致的情况下,缝隙连接功能丧失发生在 Cx43 蛋白水平降低之前。Cx43 与 ZO-1 的直接相互作用在缝隙连接调节中起着关键作用。我们通过免疫共沉淀和人类诱导多能干细胞来源的心肌细胞的互补研究发现 Ad5 感染过程中 Cx43/ZO-1 复合物的丢失通过减少 ZO-1 复合物揭示 Cx43 缝隙连接重塑。这些发现揭示了 Ad5 对缝隙连接功能的特异性靶向性,导致细胞间通讯丧失,这将导致包括感染心脏心律失常在内的危险病理状态。

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影响因子:4.69
发表时间:2020-01-07
DOI:10.1186/s12968-019-0590-z
作者列表:["Yao-Dan Liang","Yuan-Wei Xu","Wei-Hao Li","Ke Wan","Jia-Yu Sun","Jia-Yi Lin","Qing Zhang","Xiao-Yue Zhou","Yu-Cheng Chen"]

METHODS:Abstract Background Peripartum cardiomyopathy (PPCM) is rare and potentially life-threatening; its etiology remains unclear. Imaging characteristics on cardiovascular magnetic resonance (CMR) and their prognostic significance have rarely been studied. We sought to determine CMR’s prognostic value in PPCM by using T1 and T2 mapping techniques. Methods Data from 21 PPCM patients from our CMR registry database were analyzed. The control group comprised 20 healthy age-matched females. All subjects underwent comprehensive contrast-enhanced CMR. T1 and T2 mapping using modified Look-Locker inversion recovery and T2 prep balanced steady-state free precession sequences, respectively. Ventricular size and function, late gadolinium enhancement (LGE), myocardial T1 value, extracellular volume (ECV), and T2 value were analyzed. Transthoracic echocardiography was performed at baseline and during follow-up. The recovered left ventricular ejection fraction (LVEF) was defined as LVEF ≥50% on echocardiography follow-up after at least 6 months of the diagnosis. Results CMR imaging showed that the PPCM patients had severely impaired LVEF and right ventricular ejection fraction (LVEF: 26.8 ± 10.6%; RVEF: 33.9 ± 14.6%). LGE was seen in eight (38.1%) cases. PPCM patients had significantly higher native T1 and ECV (1345 ± 79 vs. 1212 ± 32 ms, P < 0.001; 33.9 ± 5.2% vs. 27.1 ± 3.1%, P < 0.001; respectively) and higher myocardial T2 value (42.3 ± 3.7 vs. 36.8 ± 2.3 ms, P < 0.001) than did the normal controls. After a median 2.5-year follow-up (range: 8 months-5 years), six patients required readmission for heart failure, two died, and 10 showed left ventricular function recovery. The LVEF-recovered group showed significantly lower ECV (30.7 ± 2.1% vs. 36.8 ± 5.6%, P = 0.005) and T2 (40.6 ± 3.0 vs. 43.9 ± 3.7 ms, P = 0.040) than the unrecovered group. Multivariable logistic regression analysis showed ECV (OR = 0.58 for per 1% increase, P = 0.032) was independently associated with left ventricular recovery in PPCM. Conclusions Compared to normal controls, PPCM patients showed significantly higher native T1, ECV, and T2. Native T1, ECV, and T2 were associated with LVEF recovery in PPCM. Furthermore, ECV could independently predict left ventricular function recovery in PPCM.

影响因子:4.69
发表时间:2020-01-05
DOI:10.1186/s12968-019-0589-5
作者列表:["Yingxia Yang","Gang Yin","Yong Jiang","Lei Song","Shihua Zhao","Minjie Lu"]

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