Nuclear remodelling: a consequence of nucleocytoplasmic traffic run amok?
Nuclear remodelling: a consequence of nucleocytoplasmic traffic run amok?
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核重塑：核质运输失控的结果？
DOI：
10.1093/cvr/cvu252
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发表时间：
2015
影响因子：
10.8
通讯作者：
Bossuyt,Julie
中科院分区：
文献类型：
--
作者：
Bossuyt,Julie
Chahineet等人的一项有趣的新研究发现，在大鼠梗死模型和人类衰竭心脏中，核结构和运输机制的改变（导致出口增加和进口减少）在肥厚发育的早期就表现出来。此外，研究发现，对增加的核出口交通进行全面封锁可以防止甚至逆转核重塑和肥厚变化。这篇文章提出了一个有趣的观点，即在心力衰竭发展过程中，核输入/输出途径本身的失败是核重构过程的基础。心脏重构是心力衰竭的一个标志，其特征是在心肌细胞水平上细胞肥大和胎儿基因程序的再激活。研究转录重编程的分子机制通常集中在相互交织的信号级联反应上，这些信号级联反应最终在细胞核中达到顶峰（例如nfat和hdac依赖途径）。转录调控的一个关键步骤是核胞质通过核孔运输关键信号成分（图1）。然而，Chahine等人从一个有趣的交通规划角度开始了他们的研究：由肥大刺激引起的交通需求增加如何影响交通速度（拥堵）和核运输路径的基础设施（道路容量和交通监管）？尽管越来越多的证据表明，几种转运机制可能同时作用于同一个信号分子，2 Chahine等人限制自己研究涉及进口蛋白和出口蛋白的经典进口和出口途径的变化。结果显示，在各种肥大模型中，核孔蛋白p62、进口蛋白（a和b）和细胞质RanBP1的表达减少（即核输入的对接和驱动力减少），出口蛋白1的表达和易位增加（即核输出的对接和易位增加）。他们的核蛋白进口测定也表明核进口途径的大小和运输速率都有所降低。Chahine等人提出的模型是，为了维持肥大过程中增加从头蛋白质合成所必需的核输出的增加，核输入必须减少（互惠移位）（图1b）。也就是说，增加的不对称交通需求可以通过起草现有的核出口车道来满足，这是一个可逆的车道系统。然而，他们的观察结果与并行运行的替代交通应对机制并不矛盾（图1c），例如道路容量的增加或交通管理的改变（例如瓶颈修改、运输方式的扩展、快速通道的创建、优先道路使用者）。考虑到在心力衰竭、3-5非输入/输出核运输、2和特定肥厚性信号转导（如HDAC激酶、nfat）的核积累中观察到的核孔组成和功能的改变，这种平行应对机制的存在当然是合理的。6,7需要进一步的研究来区分这些不同的贩运模式，并确定在不同的病理生理条件或药理反应中是否会观察到类似的贩运变化。Chahine等人还提出，治疗心力衰竭的转录策略可能成功地针对核细胞质运输过程本身，而不是被运输的货物。他们确实发现了明确的证据，表明核转运机制和功能的重排在大鼠梗死肥厚期的早期发生了改变……
An intriguing new study by Chahineet al. 1 finds that alterations in nuclear architecture and transport machinery (leading to increased export and decreased import) manifest early on, during hypertrophy development, in both a rat infarct model and human failing hearts. Moreover, it finds that general blockade of the increased nuclear export traffic can prevent or even reverse both the nuclear remodelling and hypertrophic changes. This article forwards the interesting notion that failure of the nuclear import/export pathways themselves is at the basis of the nuclear remodelling process during heart failure development. Cardiac remodelling is a hallmark of heart failure characterized at the myocyte level by cellular hypertrophy and reactivation of a fetal gene program. Studies examining the molecular mechanisms underlying the transcriptional reprogramming typically focus on the interwoven signalling cascades that culminate in the nucleus (eg NFAT-and HDAC-dependent pathways). A critical step in the transcriptional regulation here is the nucleocytoplasmic trafficking of key signalling components through the nuclear pore (Figure 1). Chahine et al., however, embarked on their study from an interesting traffic planning perspective: how does increased traffic demand induced by hypertrophic stimuli impact traffic speeds (congestion) and infrastructure of the nuclear transit pathway (road capacity and traffic regulation)? Although accumulating evidence indicates several transport mechanisms could operate on the same signal molecule in parallel, 2 Chahine et al. constrained themselves to investigating alterations in the classical import and export pathways involving importins and exportins. They show decreased expression of nucleoporin p62, importins (a and b), and cytoplasmic RanBP1 (ie reduced docking and driving force for nuclear import) and an increase in exportin-1 expression and translocation (ie increased docking and translocation for nuclear export) in various hypertrophic models. Their nuclear protein import assay also indicates a reduction in both magnitude and transport rate of the nuclear import pathway. The model proposed by Chahine et al. is that in order to sustain the increased nuclear export necessary for the increase de novo protein synthesis during hypertrophy, the nuclear import must be decreased (a reciprocal shift)(Figure 1 B). That is the increased asymmetric traffic demand is satisfied by drafting existing lanes for nuclear export, a reversible lane system. Their observations however are not inconsistent with alternate traffic coping mechanisms operating in parallel (Figure 1 C) such as an increase in road capacity or altered traffic management (eg bottleneck modification, expansion of transport modalities, creation of express lanes, preferential road users). The existence of such parallel coping mechanisms is certainly plausible given the observations of altered nuclear pore composition and function in heart failure, 3–5 importin/exportin-independent nuclear trafficking, 2 and nuclear accumulation of specific hypertrophic signal transducers (eg HDAC kinases, NFATs). 6, 7 Further study is needed to distinguish between these different traffic models and to determine whether similar trafficking changes would be observed in different pathophysiological conditions or pharmacological responses. 8 Chahine et al. also propose that transcriptional strategies for heart failure treatment might successfully target the nucleocytoplasmic trafficking process itself rather than the trafficked cargo. They do find clear evidence that the rearrangement of nuclear transport machinery and function is altered early on during the hypertrophic phase of their rat infarct …