Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria.
Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria.
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DOI：
10.1007/s00018-022-04308-z
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发表时间：
2022-05-11
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--
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补体C3最初被认为是一种血清效应蛋白，尽管最近的数据表明细胞内C3也可以调节基本的细胞过程。尽管对细胞内C3功能的兴趣越来越大，但其产生背后的机制尚未得到证实。在这项研究中，我们表明，C3可以从一个替代的翻译起始位点表达，导致C3缺乏信号肽，因此在胞质溶胶中翻译。与分泌形式相反，交替翻译的胞质C3不被糖基化，主要以还原状态存在，并被泛素-蛋白酶体系统翻转。C3也可以从内质网逆向转运到胞质溶胶中，结构上类似于分泌的C3。最后，我们证明了细胞内胞质C3可以调理上皮细胞内的侵袭性金黄色葡萄球菌，减缓空泡逃逸以及影响随后暴露于吞噬细胞的细菌存活。因此，我们的工作揭示了细胞内，胞质C3的存在和起源，并证明胞质C3在细胞内检测细胞侵入性病原体的功能。在线版本包含补充材料，可通过10.1007/s 00018 -022-04308-z获得。
Complement C3 was originally regarded as a serum effector protein, although recent data has emerged suggesting that intracellular C3 can also regulate basic cellular processes. Despite the growing interest in intracellular C3 functions, the mechanism behind its generation has not been demonstrated. In this study we show that C3 can be expressed from an alternative translational start site, resulting in C3 lacking the signal peptide, which is therefore translated in the cytosol. In contrast to the secreted form, alternatively translated cytosolic C3 is not glycosylated, is present mainly in a reduced state, and is turned over by the ubiquitin–proteasome system. C3 can also be retrotranslocated from the endoplasmic reticulum into the cytosol, structurally resembling secreted C3. Finally, we demonstrate that intracellular cytosolic C3 can opsonize invasive Staphylococcus aureus within epithelial cell, slowing vacuolar escape as well as impacting bacterial survival on subsequent exposure to phagocytes. Our work therefore reveals the existence and origin of intracellular, cytosolic C3, and demonstrates functions for cytosolic C3 in intracellular detection of cytoinvasive pathogens. The online version contains supplementary material available at 10.1007/s00018-022-04308-z.
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