Venditti Rossella, Scanu Tiziana, Santoro Michele, Di Tullio Giuseppe, Spaar Alexander, Gaibisso Renato, Beznoussenko Galina V, Mironov Alexander A, Mironov Alexander, Zelante Leopoldo, Piemontese Maria Rosaria, Notarangelo Angelo, Malhotra Vivek, Vertel Barbara M, Wilson Cathal, De Matteis Maria Antonietta
Telethon Institute of Genetics and Medicine, Naples, Italy.
Science. 2012 Sep 28;337(6102):1668-72. doi: 10.1126/science.1224947.
Newly synthesized proteins exit the endoplasmic reticulum (ER) via coat protein complex II (COPII) vesicles. Procollagen (PC), however, forms prefibrils that are too large to fit into typical COPII vesicles; PC thus needs large transport carriers, which we term megacarriers. TANGO1 assists PC packing, but its role in promoting the growth of megacarriers is not known. We found that TANGO1 recruited Sedlin, a TRAPP component that is defective in spondyloepiphyseal dysplasia tarda (SEDT), and that Sedlin was required for the ER export of PC. Sedlin bound and promoted efficient cycling of Sar1, a guanosine triphosphatase that can constrict membranes, and thus allowed nascent carriers to grow and incorporate PC prefibrils. This joint action of TANGO1 and Sedlin sustained the ER export of PC, and its derangement may explain the defective chondrogenesis underlying SEDT.
新合成的蛋白质通过II型被膜小泡蛋白复合物（COPII）囊泡离开内质网（ER）。然而，前胶原（PC）会形成太大而无法装入典型COPII囊泡的前原纤维；因此，PC需要大型运输载体，我们将其称为巨型载体。TANGO1协助PC包装，但其在促进巨型载体生长中的作用尚不清楚。我们发现，TANGO1招募了Sedlin，这是一种在迟发性脊椎骨骺发育不良（SEDT）中存在缺陷的TRAPP成分，并且Sedlin是PC从内质网输出所必需的。Sedlin结合并促进了Sar1（一种可收缩膜的鸟苷三磷酸酶）的高效循环，从而使新生载体得以生长并纳入PC前原纤维。TANGO1和Sedlin的这种联合作用维持了PC从内质网的输出，其紊乱可能解释了SEDT潜在的软骨生成缺陷。
