Disparate Intracellular Processing of Human IL-12 Preprotein Subunits: Atypical Processing of the P35 Signal Peptide1
Disparate Intracellular Processing of Human IL-12 Preprotein Subunits: Atypical Processing of the P35 Signal Peptide1
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人 IL-12 前蛋白亚基的不同细胞内加工：P35 信号肽的非典型加工1
作者：
F. J. Murphy;M. Hayes;P. Burd
IL-12是由APC产生的异源二聚体细胞因子，其关键地调节细胞介导的免疫。由于其在免疫应答期间的关键功能，IL-12的产生受到严格调节，部分通过其p35亚基的转录控制，这需要IFN-γ的分化作用来表达。为了确定IL-12产生的转录后方面是否可能受到调节，我们检查了每个亚基的细胞内蛋白质加工。我们在这里报告说，p40和p35亚基处理不同的途径。而p40的加工符合信号肽去除伴随着易位到内质网（ER）的共翻译模型，p35的加工不。易位的p35前蛋白到ER不伴随着切割的信号肽，而是通过两个连续的切割发生的p35信号肽的去除。第一次切割发生在ER内，并且切割位点定位于信号肽的疏水区域的中间。虽然前蛋白在进入ER时被糖基化，但其糖基化状态不影响初级切割。随后，p35信号肽的剩余部分通过第二次切割去除，可能涉及金属蛋白酶，伴随着额外的糖基化和分泌。第二切割位点的突变或衣霉素抑制糖基化可抑制分泌。相反，p40分泌不受糖基化抑制的影响。我们的研究结果表明，IL-12亚基是由不同的途径处理，并提出了新的方式来调节IL-12的生产。
IL-12 is a heterodimeric cytokine produced by APC that critically regulates cell-mediated immunity. Because of its crucial function during immune responses, IL-12 production is stringently regulated, in part through transcriptional control of its p35 subunit, which requires the differentiative effects of IFN-γ for expression. To determine whether post-transcriptional aspects of IL-12 production might be regulated, we examined intracellular protein processing of each subunit. We report here that p40 and p35 subunits are processed by disparate pathways. Whereas processing of p40 conforms to the cotranslational model of signal peptide removal concomitant with translocation into the endoplasmic reticulum (ER), processing of p35 does not. Translocation of the p35 preprotein into the ER was not accompanied by cleavage of the signal peptide; rather, removal of the p35 signal peptide occurred via two sequential cleavages. The first cleavage took place within the ER, and the cleavage site localized to the middle of the hydrophobic region of the signal peptide. Although the preprotein was glycosylated upon entry into the ER, its glycosylation status did not affect primary cleavage. Subsequently, the remaining portion of the p35 signal peptide was removed by a second cleavage, possibly involving a metalloprotease, concomitant with additional glycosylation and secretion. Secretion could be inhibited by mutation of the second cleavage site or by inhibition of glycosylation with tunicamycin. In contrast, p40 secretion was not affected by inhibition of glycosylation. Our findings demonstrate that IL-12 subunits are processed by disparate pathways and suggest new modalities for regulation of IL-12 production.
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作者：
Santhanam,U;Ghrayeb,J;Sehgal,PB;May,LT
通讯作者：
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DOI：
10.1073/pnas.94.22.12041
发表时间：
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影响因子：
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