Calpains promote α2β1 integrin turnover in nonrecycling integrin pathway.
Calpains promote α2β1 integrin turnover in nonrecycling integrin pathway.
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DOI：
10.1091/mbc.e11-06-0548
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发表时间：
2012-02
影响因子：
3.3
通讯作者：
Marjomäki V
中科院分区：
文献类型：
--
作者：
Rintanen N;Karjalainen M;Alanko J;Paavolainen L;Mäki A;Nissinen L;Lehkonen M;Kallio K;Cheng RH;Upla P;Ivaska J;Marjomäki V
一种新的病毒和整合素聚集特异性途径将整合素从其正常的内/外胞运输转移到非循环降解内体途径。α2β1整联蛋白的聚集导致整联蛋白重新分布到核周内体，导致钙蛋白酶促进的整联蛋白周转增强。胶原受体整合素在质膜和内体之间循环，并促进局灶性粘连的形成和周转。相反，α2β1整联蛋白与抗体或人类病原体埃可病毒1（EV 1）的聚集导致α2整联蛋白重新分布到核周多泡体（α2-MVB）。我们在这里表明，内化成簇的α2整联蛋白保留在α2-MVB中，并且不会再循环回质膜。相反，与未成簇的α2整联蛋白的缓慢周转相比，受体成簇和内化导致α2β1整联蛋白的加速下调。EV 1感染或整合素降解与蛋白酶体或自噬体过程无关，与溶酶体途径无显著相关性。相反，降解依赖于钙蛋白酶，因此它被钙蛋白酶抑制剂阻断。我们发现活性钙蛋白酶存在于α2-MVB中，内化的成簇α2β1整合素与钙蛋白酶-1共沉淀，钙蛋白酶酶可以降解α2β1整合素。总之，我们确定了一种新的病毒和聚集特异性途径，将α2β1整合素从其正常的内/外胞运输转移到非再循环的钙蛋白酶依赖性降解内体途径。
A novel virus- and integrin clustering–specific pathway diverts integrin from its normal endo/exocytic traffic to a nonrecycling degradative endosomal route. Clustering of α2β1 integrin causes redistribution of the integrin to perinuclear endosomes, leading to enhanced integrin turnover promoted by calpains. Collagen receptor integrins recycle between the plasma membrane and endosomes and facilitate formation and turnover of focal adhesions. In contrast, clustering of α2β1 integrin with antibodies or the human pathogen echovirus 1 (EV1) causes redistribution of α2 integrin to perinuclear multivesicular bodies, α2-MVBs. We show here that the internalized clustered α2 integrin remains in α2-MVBs and is not recycled back to the plasma membrane. Instead, receptor clustering and internalization lead to an accelerated down-regulation of α2β1 integrin compared to the slow turnover of unclustered α2 integrin. EV1 infection or integrin degradation is not associated with proteasomal or autophagosomal processes and shows no significant association with lysosomal pathway. In contrast, degradation is dependent on calpains, such that it is blocked by calpain inhibitors. We show that active calpain is present in α2-MVBs, internalized clustered α2β1 integrin coprecipitates with calpain-1, and calpain enzymes can degrade α2β1 integrin. In conclusion, we identified a novel virus- and clustering-specific pathway that diverts α2β1 integrin from its normal endo/exocytic traffic to a nonrecycling, calpain-dependent degradative endosomal route.