Major histocompatibility complex class II-associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L.
The invariant chain (Ii) is associated with major histocompatibility complex class II molecules during early stages of their intracellular transport. In an acidic endosomal/lysosomal compartment, it is proteolytically cleaved and removed from class II heterodimers. Participation of aspartic and cysteine proteases has been observed in in vitro degradation of Ii, but the specific enzymes responsible for its in vivo processing are as yet undefined. We have previously isolated a noncovalent complex of the lysosomal cysteine protease cathepsin L with a peptide fragment derived from the p41 form of Ii from human kidney. Here we show that this Ii fragment, which is identical to the alternatively spliced segment of p41, is a very potent competitive inhibitor of cathepsin L (equilibrium inhibition constant Ki = 1.7 X 10(-12) M). It inhibits two other cysteine proteases, cathepsin H and papain, but to much lesser extent. Cysteine proteases cathepsins B, C, and S, as well as representatives of serine, aspartic, and metalloproteases, are not inhibited at all. These findings suggest a novel role for p41 in the regulation of various proteolytic activities during antigen processing and presentation. The Ii inhibitory fragment shows no sequence homology with the known cysteine protease inhibitors, and may, therefore, represent a new class.
Bevec
T
T
Department of Biochemistry and Molecular Biology, Jozef Stefan Institute, Ljubljana, Slovenia.
Stoka
V
V
Pungercic
G
G
Dolenc
I
I
Turk
V
V
D000595:Amino Acid Sequence; D000944:Antigens, Differentiation, B-Lymphocyte / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010450:Endopeptidases; D000949:Histocompatibility Antigens Class II / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000737:chemistry*; D008247:Lysosomes / Q000201:enzymology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding
D000944:Antigens, Differentiation, B-Lymphocyte; D015853:Cysteine Proteinase Inhibitors; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; C045084:invariant chain; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L