Bevec T, Stoka V, Pungercic G, Dolenc I, Turk V
Department of Biochemistry and Molecular Biology, Jozef Stefan Institute, Ljubljana, Slovenia.
J Exp Med. 1996 Apr 1;183(4):1331-8. doi: 10.1084/jem.183.4.1331.
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.
恒定链（Ii）在细胞内运输的早期阶段与主要组织相容性复合体II类分子相关联。在酸性内体/溶酶体区室中，它被蛋白酶水解并从II类异二聚体中去除。在Ii的体外降解过程中已观察到天冬氨酸蛋白酶和半胱氨酸蛋白酶的参与，但负责其体内加工的具体酶尚未确定。我们之前从人肾中分离出一种溶酶体半胱氨酸蛋白酶组织蛋白酶L与源自Ii的p41形式的肽片段的非共价复合物。在此我们表明，这个与p41的可变剪接片段相同的Ii片段是组织蛋白酶L的一种非常有效的竞争性抑制剂（平衡抑制常数Ki = 1.7×10^(-12) M）。它对另外两种半胱氨酸蛋白酶组织蛋白酶H和木瓜蛋白酶也有抑制作用，但程度要小得多。半胱氨酸蛋白酶组织蛋白酶B、C和S，以及丝氨酸、天冬氨酸和金属蛋白酶的代表则完全不受抑制。这些发现表明p41在抗原加工和呈递过程中对各种蛋白水解活性的调节中具有新作用。Ii抑制片段与已知的半胱氨酸蛋白酶抑制剂没有序列同源性，因此可能代表一个新类别。
