GRASP65 and GRASP55 sequentially promote the transport of C-terminal valine-bearing cargos to and through the Golgi complex.
The Golgi matrix proteins GRASP65 and GRASP55 have recognized roles in maintaining the architecture of the Golgi complex, in mitotic progression and in unconventional protein secretion whereas, surprisingly, they have been shown to be dispensable for the transport of commonly used reporter cargo proteins along the secretory pathway. However, it is becoming increasingly clear that many trafficking machineries operate in a cargo-specific manner, thus we have investigated whether GRASPs may control the trafficking of selected classes of cargo. We have taken into consideration the C-terminal valine-bearing receptors CD8alpha and Frizzled4 that we show bind directly to the PSD95-DlgA-zo-1 (PDZ) domains of GRASP65 and GRASP55. We demonstrate that both GRASPs are needed sequentially for the efficient transport to and through the Golgi complex of these receptors, thus highlighting a novel role for the GRASPs in membrane trafficking. Our results open new perspectives for our understanding of the regulation of surface expression of a class of membrane proteins, and suggests the causal mechanisms of a dominant form of autosomal human familial exudative vitreoretinopathy that arises from the Frizzled4 mutation involving its C-terminal valine.
D'Angelo
Giovanni
G
Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
Prencipe
Libera
L
Iodice
Luisa
L
Beznoussenko
Galina
G
Savarese
Marco
M
Marra
Pierfrancesco
P
Di Tullio
Giuseppe
G
Martire
Gianluca
G
De Matteis
Maria Antonietta
MA
Bonatti
Stefano
S
D000818:Animals; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D000077614:Golgi Matrix Proteins; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014633:Valine / Q000378:metabolism*
D016827:CD8 Antigens; C431698:CD8alpha antigen; C108705:GORASP1 protein, human; C122048:GORASP2 protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D014633:Valine