View Program - asbmb

74
TRAPP is required for ER exit of procollagen by
controlling the Sar1 cycle
Rossella Venditti 1 , Tiziana Scanu 3 , Renato Gaibisso 4 , Giuseppe Di Tullio 2 , Cathal Wilson 2 , Maria
Antonietta De Matteis 1, 2 .
Telethon Institute of Genetiics and Medicine (TIGEM), Naples, ITALY 1 , Department of Cell
Biology and Oncology, Consorzio Mario Negri Sud, Santa Maria Imbaro (CH), ITALY 2 , Division
of Cell Biology,The Netherlands Cancer Institute (NKI-AVL), Amsterdam The Netherlands 3 ,
Institute of Cell Biology, ETH Zurich, Switzerland 4
Abstract:
The study of inherited human disorders, including those involving membrane trafficking, can
provide important hints towards an understanding of the physiological context, molecular
pathways, and actual functional role of the gene products affected. On this basis, we have
investigated the role of sedlin, a conserved component of TRAPP, a multimolecular complex so
far involved in the heterotypic tethering of ER-derived vesicles to the Golgi membranes in yeast
and in the homotypic tethering of ER-derived vesicles in mammals. Genetic defects of sedlin
result in spondyloepiphyseal dysplasia tarda (SEDT), a condition characterised by short stature,
flattening of the vertebrae, and premature osteoarthritis. Inherited epiphyseal dysplasias are
genetically heterogenous disorders of chondrocytes, which include defects of secretory
chondrocyte cargoes (matrilin, aggrecan, collagens II and IX), cargo processing apparatus
(chondroitin sulfotransferase and sulfate transporter), and the trafficking machinery (sedlin).
Prompted by the concept that defects in extracellular matrix components and in sedlin can
cause similar phenotypes, and by the observation that chondrocytes from SEDT patients show
indirect signs of impaired trafficking at the ER (i.e. dilated ER), we have analysed the role of
sedlin and other TRAPP components in the trafficking of neosynthesised procollagen. We show
that sedlin and the whole TRAPP complex are selectively required for procollagen to exit the ER,
while they are not essential for ER exit of small soluble and membrane-associated cargoes. We
have also identified the molecular mechanism underlying this role of TRAPP and sedlin in their
ability to control the membrane–cytosol cycle of COPII and Sar1 at the ER exit sites.