Tetraspanin CD63 promotes targeting and lysosomal proteolysis of membrane-type 1 matrix metalloproteinase.
Membrane-type 1 matrix metalloproteinase (MT1-MMP) is known to be internalized from cell surface, however, the fate of internalized MT1-MMP is still unknown. Here we demonstrate that at least a part of internalized MT1-MMP is targeted for lysosomal proteolysis. Treatment with an inhibitor of lysosomal proteinases chloroquine suppressed degradation of internalized MT1-MMP and induced accumulation of MT1-MMP in CD63-positive lysosomes. Ectopic expression of CD63 accelerated degradation of MT1-MMP, which was blocked by chloroquine. MT1-MMP, and CD63 were shown to form a complex through hemopexin-like domain of MT1-MMP and N-terminal region of CD63, and thus accelerated degradation of MT1-MMP was not observed with mutants lacking these domains. CD63 mutant lacking lysosomal targeting motif was unable to promote MT1-MMP degradation. These results suggest that CD63 regulates MT1-MMP by targeting to lysosomes.
Takino
Takahisa
T
Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, 920-0934, Kanazawa, Japan.
Miyamori
Hisashi
H
Kawaguchi
Noriko
N
Uekita
Takamasa
T
Seiki
Motoharu
M
Sato
Hiroshi
H
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D002460:Cell Line; D004285:Dogs; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D018613:Microscopy, Confocal; D010980:Platelet Membrane Glycoproteins / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D021381:Protein Transport; D017384:Sequence Deletion; D060149:Tetraspanin 30
D015703:Antigens, CD; C554586:CD63 protein, human; D010980:Platelet Membrane Glycoproteins; D060149:Tetraspanin 30; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases