Cysteine protease-mediated cytoskeleton interactions with LFA-1 promote T-cell morphological changes.
T cells migrate through restrictive barriers in a protease-independent, amoeboid fashion that is characterized by morphological cell polarization. The interaction of cysteine-dependent carboxypeptidase cathepsin X with beta(2) integrin LFA-1 (lymphocyte function associated antigen 1) induces T-cell morphological changes, displaying into a 3D extracellular matrix a cytoplasmic projection termed a uropod. In the present study we show that inhibition of cathepsin X and a cysteine-dependent endopeptidase, cathepsin L, markedly inhibits T-cell actin polymerization, shape polarization, and chemotaxis. We propose that cathepsin L promotes T-cell migration associated processes by activating procathepsin X in the endolysosomal vesicles near the cell membrane and at the peak of the uropod, where both proteases were colocalized. We show that active cathepsin X modifies the beta(2) cytoplasmic tail of LFA-1 in the uropod, promoting its high affinity conformation. We suggest that LFA-1 cleavage contributes to the conformational change in the cytoplasmic tail, promoting the binding of the cytoskeletal protein talin. This interaction is restricted to the uropod and results in the stabilization of this region, promoting LFA-1-mediated cell uropod elongation.
Jevnikar
Zala
Z
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
Obermajer
Natasa
N
Kos
Janko
J
D000199:Actins / Q000378:metabolism*; D002403:Cathepsins / Q000378:metabolism*; D016764:Cell Polarity; D022081:Cell Surface Extensions / Q000378:metabolism; D002633:Chemotaxis; D057056:Cysteine Proteases / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D055503:Protein Multimerization; D013601:T-Lymphocytes / Q000201:enzymology / Q000648:ultrastructure*; D016608:Talin / Q000378:metabolism
D000199:Actins; D016169:Lymphocyte Function-Associated Antigen-1; D016608:Talin; D002403:Cathepsins; D057056:Cysteine Proteases