Processing and turnover of the Hedgehog protein in the endoplasmic reticulum.
Processing and turnover of the Hedgehog protein in the endoplasmic reticulum.
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DOI：
10.1083/jcb.201008090
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发表时间：
2011-03-07
期刊：
影响因子：
--
通讯作者：
Salic A
中科院分区：
文献类型：
--
作者：
Chen X;Tukachinsky H;Huang CH;Jao C;Chu YR;Tang HY;Mueller B;Schulman S;Rapoport TA;Salic A
Hedgehog配体从其前体蛋白的自催化加工依赖于蛋白质二硫键异构酶和ER相关降解。Hedgehog（Hh）信号通路在后生动物的发育过程中具有重要的作用。Hh配体通过自切割由前体产生，其需要蛋白质的C-末端部分中的游离半胱氨酸，并导致胆固醇修饰的配体和C-末端片段的产生。在本文中，我们证明，这些反应发生在内质网（ER）。催化半胱氨酸需要与保守半胱氨酸形成二硫桥，其随后被蛋白质二硫键异构酶还原。C-末端片段的产生之后是其ER相关降解（ERAD），提供了组成性降解的内源性管腔ERAD底物的第一个实例。这一过程需要泛素连接酶Hrd 1、其伴侣Sel 1、胞浆腺苷三磷酸酶p97和蛋白酶体的降解。Hh的加工缺陷突变体被相同的ERAD组分降解。因此，Hh前体的加工与其快速降解竞争，解释了加工缺陷突变体（如导致人类前脑无裂畸形的突变体）的Hh信号传导受损。
Autocatalytic processing of the Hedgehog ligand from its precursor protein relies on protein disulfide isomerase and ER-associated degradation. The Hedgehog (Hh) signaling pathway has important functions during metazoan development. The Hh ligand is generated from a precursor by self-cleavage, which requires a free cysteine in the C-terminal part of the protein and results in the production of the cholesterol-modified ligand and a C-terminal fragment. In this paper, we demonstrate that these reactions occur in the endoplasmic reticulum (ER). The catalytic cysteine needs to form a disulfide bridge with a conserved cysteine, which is subsequently reduced by protein disulfide isomerase. Generation of the C-terminal fragment is followed by its ER-associated degradation (ERAD), providing the first example of an endogenous luminal ERAD substrate that is constitutively degraded. This process requires the ubiquitin ligase Hrd1, its partner Sel1, the cytosolic adenosine triphosphatase p97, and degradation by the proteasome. Processing-defective mutants of Hh are degraded by the same ERAD components. Thus, processing of the Hh precursor competes with its rapid degradation, explaining the impaired Hh signaling of processing-defective mutants, such as those causing human holoprosencephaly.
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