Major histocompatibility complex class II-associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L
Major histocompatibility complex class II-associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L
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DOI：
10.1084/jem.183.4.1331
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发表时间：
1996-04-01
影响因子：
15.3
通讯作者：
Turk, V
中科院分区：
文献类型：
--
作者：
Bevec, T;Stoka, V;Turk, V
不变链 (Ii) 在细胞内运输的早期阶段与主要组织相容性复合物 II 类分子相关。在酸性内体/溶酶体区室中，它被蛋白水解裂解并从 II 类异二聚体中去除。已观察到天冬氨酸和半胱氨酸蛋白酶参与 Ii 的体外降解，但负责其体内加工的特定酶尚未确定。我们之前已经分离出溶酶体半胱氨酸蛋白酶组织蛋白酶 L 与源自人肾 Ii 的 p41 形式的肽片段的非共价复合物。在这里，我们证明这个 Ii 片段与 p41 的选择性剪接片段相同，是组织蛋白酶 L 的非常有效的竞争性抑制剂（平衡抑制常数 K-i = 1.7 X 10(-12) M）。它抑制另外两种半胱氨酸蛋白酶：组织蛋白酶 H 和木瓜蛋白酶，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，完全不受抑制。这些发现表明 p41 在抗原加工和呈递过程中调节各种蛋白水解活性中发挥新作用。 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。
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 K-i = 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.