Distinct functions of human MVB12A and MVB12B in the ESCRT-I dependent on their posttranslational modifications.
ESCRT-I, which mediates the sorting of ubiquitinated cargo protein from the plasma membrane to the endosomal vesicle, comprises a heterotetramer of TSG101 (Vps23), Vps28, Vps37 and MVB12 protein. In humans, the structurally similar subtypes MVB12A and MVB12B are subunits of ESCRT-I. However, no functional description of these proteins has been described. Here we show the differing effects of tyrosine phosphorylation and ubiquitination of both MVB12 proteins on their respective functions. As noted in our previous study, Tyr204 phosphorylation of MVB12A in response to epidermal growth factor (EGF) stimulation affects binding to CD2AP, which regulates the amounts of EGF receptor bound to ESCRT-I. Strikingly, ubiquitination of Lys264 and Lys290 of MVB12B was induced and led to the instability and inclusion of MVB12B in COS-7 cells. These ubiquitinations increased upon EGF stimulation, which was regulated by the phosphorylations of Tyr241 and Tyr243 of MVB12B. Furthermore, MVB12A was also involved in the aggregation-prone proteins of MVB12B. These results suggest that the expression of MVB12B may be normally suppressed through the ubiquitin-proteasome pathway that simultaneously regulates the fate of MVB12A and the functions of ESCRT-I.
Tsunematsu
Takumi
T
Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
Yamauchi
Emiko
E
Shibata
Hideki
H
Maki
Masatoshi
M
Ohta
Takeshi
T
Konishi
Hiroaki
H
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits; D014443:Tyrosine / Q000378:metabolism; D054875:Ubiquitination; D033921:Vesicular Transport Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D056827:Endosomal Sorting Complexes Required for Transport; C514895:MVB12A protein, human; C552120:MVB12B protein, human; D010750:Phosphoproteins; D021122:Protein Subunits; D033921:Vesicular Transport Proteins; D014443:Tyrosine; D004815:Epidermal Growth Factor; D046988:Proteasome Endopeptidase Complex; D008239:Lysine