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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage
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SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage

机译：SPLUNC1通过保护ENaC免受蛋白水解裂解来调节气道表面液量

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摘要

Many epithelia, including the superficial epithelia of the airways, are thought to secrete "volume sensors," which regulate the volume of the mucosal lining fluid. The epithelial Na~+ channel (ENaC) is often the rate limiting factor in fluid absorption, and must be cleaved by extracellular and/or intracellular proteases before it can conduct Na~+ and absorb excess mucosal liquid, a process that can be blocked by proteases inhibitors. In the airways, airway surface liquid dilution or removal activates ENaC. Therefore, we hypothesized that endogenous proteases are membrane-anchored, whereas endogenous pro-teolysis inhibitors are soluble and can function as airway surface liquid volume sensors to inhibit ENaC activity. Using a proteomic approach, we identified short palate, lung, and nasal epithelial clone (SPLUNQ1 as a candidate volume sensor. Recombinant SPLUNC1 inhibited ENaC activity in both human bronchial epithelial cultures and Xenopus oocytes. Knockdown of SPLUNC1 by shRNA resulted in a failure of bronchial epithelial cultures to regulate ENaC activity and airway surface liquid volume, which was restored by adding recombinant SPLUNC1 to the airway surface liquid. Despite being able to inhibit ENaC, recombinant SPLUNC1 had little effect on extracellular serine protease activity. However, SPLUNC1 specifically bound to ENaC, preventing its cleavage and activation by serine proteases. SPLUNC1 is highly expressed in the airways, as well as in colon and kidney. Thus, we propose that SPLUNC1 is secreted onto mucosal surfaces as a soluble volume sensor whose concentration and dilution can regulate ENaC activity and mucosal volumes, including that of airway surface liquid.
机译：许多上皮细胞，包括气道浅表上皮细胞，被认为会分泌“体积传感器”，从而调节粘膜衬里液的体积。上皮Na〜+通道（ENaC）通常是液体吸收的速率限制因素，必须先被细胞外和/或细胞内蛋白酶裂解，然后才能传导Na〜+并吸收过量的粘膜液体，这一过程可以被阻断蛋白酶抑制剂。在气道中，气道表面液体的稀释或去除会激活ENaC。因此，我们假设内源蛋白酶是膜锚定的，而内源蛋白水解抑制剂是可溶的，并且可以作为气道表面液量传感器来抑制ENaC活性。使用蛋白质组学方法，我们确定了短pa，肺和鼻上皮克隆（SPLUNQ1为候选体积传感器。重组SPLUNC1抑制了人支气管上皮培养物和非洲爪蟾卵母细胞中的ENaC活性。通过在气道表面液中加入重组SPLUNC1来恢复上皮培养物以调节ENaC活性和气道表面液量，尽管重组SPLUNC1能够抑制ENaC，但对细胞外丝氨酸蛋白酶活性的影响很小，但SPLUNC1与ENaC特异性结合SPLUNC1在气道，结肠和肾脏中高度表达，因此，我们提出SPLUNC1作为浓度和稀释度可调节ENaC活性的可溶性体积传感器分泌到粘膜表面。和粘膜体积，包括气道表面液体的体积。

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    AguStin Garcia-Caballero; Julia E. Rasmussen; Erol Gaillard; Michael J. Watson; John C. Olsen; Scott H. Donaldson; M. Jackson Stutts; Robert Tarran;

  • 作者单位

    Cystic Fibrosis/Pulmonary Research and Treatment Center, Thurston-Bowles Building, University of North Carolina, Chapel Hill, NC 27599-7248;

    Cystic Fibrosis/Pulmonary Research and Treatment Center, Thurston-Bowles Building, University of North Carolina, Chapel Hill, NC 27599-7248;

    Cystic Fibrosis/Pulmonary Research and Treatment Center, Thurston-Bowles Building, University of North Carolina, Chapel Hill, NC 27599-7248;

    Cystic Fibrosis/Pulmonary Research and Treatment Center, Thurston-Bowles Building, University of North Carolina, Chapel Hill, NC 27599-7248;

    Cystic Fibrosis/Pulmonary Research and Treatment Center, Thurston-Bowles Building, University of North Carolina, Chapel Hill, NC 27599-7248;

    Cystic Fibrosis/Pulmonary Research and Treatment Center, Thurston-Bowles Building, University of North Carolina, Chapel Hill, NC 27599-7248;

    Cystic Fibrosis/Pulmonary Research and Treatment Center, Thurston-Bowles Building, University of North Carolina, Chapel Hill, NC 27599-7248;

    Cystic Fibrosis/Pulmonary Research and Treatment Center, Thurston-Bowles Building, University of North Carolina, Chapel Hill, NC 27599-7248;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cystic fibrosis; epithelial; sodium; kidney; colon;

    机译：囊性纤维化;上皮钠;肾;结肠;

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