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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Integrins α1β1 And α2β1 Are Receptors For The Rotavirus Enterotoxin
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Integrins α1β1 And α2β1 Are Receptors For The Rotavirus Enterotoxin

机译：整合素α1β1和α2β1是轮状病毒肠毒素的受体

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摘要

Rotavirus NSP4 is a viral enterotoxin capable of causing diarrhea in neonatal mice. This process is initiated by the binding of extracellular NSP4 to target molecule(s) on the cell surface that triggers a signaling cascade leading to diarrhea. We now report that the integrins α1β1 and α2β1 are receptors for NSP4. NSP4 specifically binds to the α1 and α2 I domains with apparent K_d = 1-2.7 μM. Binding is mediated by the I domain metal ion-dependent adhesion site motif, requires Mg~(2+) or Mn~(2+), is abolished with EDTA, and an NSP4 point mutant, E_(120A, fails to bind oil integrin I domain. NSP4 has two distinct integrin interaction domains. NSP4 amino acids 114-130 are essential for binding to the I domain, and NSP4 peptide 114-135 blocks binding of the natural ligand, collagen I, to integrin α2. NSP4 amino acids 131-140 are not associated with the initial binding to the I domain, but elicit signaling that leads to the spreading of attached C2C12-α2 cells, mouse myoblast cells stably expressing the human α2 integrin. NSP4 colocalizes with integrin α2 on the basolateral surface of rotavirus-infected polarized intestinal epithelial (Caco-2) cells as well as surrounding noninfected cells. NSP4 mutants that fail to bind or signal through integrin α2 are attenuated in diarrhea induction in neonatal mice. These results indicate that NSP4 interaction with integrin α1 and α2 is an important component of enterotoxin function and rotavirus patho-genesis, further distinguishing this viral virulence factor from other microbial enterotoxins.
机译：轮状病毒NSP4是一种病毒性肠毒素，可引起新生小鼠腹泻。该过程是由细胞外NSP4与细胞表面上的靶分子结合而引发的，从而触发导致腹泻的信号级联反应。现在我们报道，整联蛋白α1β1和α2β1是NSP4的受体。 NSP4以明显的K_d = 1-2.7μM特异性结合到α1和α2I域。结合由I域金属离子依赖性粘附位点基序介导，需要Mg〜（2+）或Mn〜（2+），被EDTA废除，NSP4点突变体E_（120A）无法结合油整合素NSP4具有两个不同的整联蛋白相互作用结构域，NSP4氨基酸114-130对于结合I结构域必不可少，NSP4肽114-135阻止天然配体胶原蛋白I与整联蛋白α2结合，NSP4氨基酸131 -140与最初与I结构域的结合无关，但会引起信号传导，导致附着的C2C12-α2细胞扩散，小鼠成肌细胞稳定表达人α2整合素； NSP4与整合素α2在轮状病毒的基底外侧表面共定位感染的极化小肠上皮细胞（Caco-2）以及周围未感染的细胞。未能通过整合素α2结合或发出信号的NSP4突变体在新生小鼠腹泻诱导中减弱了。这些结果表明NSP4与整合素α1和α2的相互作用是一个肠毒素功能和轮状病毒发病机理的重要组成部分，进一步将这种病毒毒力因子与其他微生物肠毒素区分开来。

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