Enzymatic reduction of disulfide bonds in lysosomes: Characterization of a Gamma-interferon-inducible lysosomal thiol reductase (GILT)
Enzymatic reduction of disulfide bonds in lysosomes: Characterization of a Gamma-interferon-inducible lysosomal thiol reductase (GILT)
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DOI：
10.1073/pnas.97.2.745
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发表时间：
2000-01-18
影响因子：
11.1
通讯作者：
Cresswell, P
中科院分区：
文献类型：
--
作者：
Arunachalam, B;Phan, UT;Cresswell, P
内化进入内吞途径的蛋白质通常会被降解。有效的蛋白质降解需要由溶酶体内的酸性条件引起的变性，以及链间和链内二硫键的减少。胞浆还原是由硫氧还蛋白介导的，但溶酶体还原的机制尚不清楚，我们在这里描述了一种溶酶体硫醇还原酶，它在低pH条件下活性最高，能够在体内和体外催化二硫键还原。通过突变确定的活性部位由一对半胱氨酸残基组成，由两个氨基酸隔开，类似于硫氧还蛋白家族的其他酶。该酶是一种作为前体合成的可溶性糖蛋白。通过甘露糖6-磷酸受体进入内体/溶酶体系统后，N-末端和C-末端的前体序列被去除。该酶在抗原提呈细胞中结构性表达，并在其他类型的细胞中由干扰素-γ诱导表达，这表明该酶在抗原加工中具有潜在的重要作用。
Proteins internalized into the endocytic pathway are usually degraded. Efficient proteolysis requires denaturation, induced by acidic conditions within lysosomes, and reduction of inter- and intrachain disulfide bonds. Cytosolic reduction is mediated enzymatically by thioredoxin, but the mechanism of lysosomal reduction is unknown, We describe here a lysosomal thiol reductase optimally active at low pH and capable of catalyzing disulfide bond reduction both in vivo and in vitro. The active site, determined by mutagenesis, consists of a pair of cysteine residues separated by two amino acids, similar to other enzymes of the thioredoxin family. The enzyme is a soluble glycoprotein that is synthesized as a precursor. After delivery into the endosomal/lysosomal system by the mannose 6-phosphate receptor, N- and C-terminal prosequences are removed. The enzyme is expressed constitutively in antigen-presenting cells and induced by IFN-gamma in other cell types, suggesting a potentially important role in antigen processing.