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首页> 外文期刊>Molecular and Cellular Biology >Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection
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Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection

机译：SHARPIN和HOIL-1L的Npl4锌指结构域在线性泛素链装配复合物介导的细胞死亡保护中的差异参与。

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The linear ubiquitin chain assembly complex (LUBAC) participates in NF-κB activation and cell death protection. Loss of any of the three LUBAC subunits (catalytic HOIP, accessory HOIL-1L, or accessory SHARPIN subunit) leads to distinct phenotypes in mice and human. cpdm mice (chronic proliferative dermatitis in mice [cpdm]) that lack SHARPIN exhibit chronic inflammatory phenotypes, whereas HOIL-1L knockout mice exhibit no overt phenotypes, despite sharing highly homologous ubiquitin-like (UBL) and Npl4 zinc finger (NZF) domains. Here, we intercrossed mice lacking HOIL-1L and SHARPIN and found that reduction of HOIL-1L in cpdm mice exacerbated inflammatory phenotypes without affecting characteristic features of cpdm disease, whereas reduction of SHARPIN in HOIL-1L knockout mice provoked no overt phenotypes. Hence, loss of SHARPIN and reduction of LUBAC triggers cpdm phenotypes. We found that the NZF domain of SHARPIN, but not that of HOIL-1L, is critical for effective protection from programmed cell death by enhancing the recruitment of LUBAC to the activated TNFR complex. The binding activity to K63-linked ubiquitin chains that the NZF domain of SHARPIN, but not that of HOIL-1L, possesses appears to be involved in the recruitment. Thus, selective recognition of ubiquitin chains by NZFs in LUBAC underlies the regulation of LUBAC function.
机译：线性泛素链组装复合体（LUBAC）参与NF-κB激活和细胞死亡保护。三个LUBAC亚基（催化性HOIP，辅助性HOIL-1L或辅助性SHARPIN亚基）中任何一个的丢失都会在小鼠和人类中导致不同的表型。缺少SHARPIN的cpdm小鼠（小鼠中的慢性增生性皮炎[cpdm]）表现出慢性炎性表型，而HOIL-1L基因敲除小鼠尽管具有高度同源的泛素样（UBL）和Npl4锌指（NZF）结构域，却没有明显的表型。在这里，我们交叉了缺少HOIL-1L和SHARPIN的小鼠，发现cpdm小鼠中HOIL-1L的减少加重了炎症表型，而没有影响cpdm疾病的特征，而HOIL-1L敲除小鼠中SHARPIN的减少没有引起明显的表型。因此，SHARPIN的丢失和LUBAC的减少会触发cpdm表型。我们发现，SHARPIN的NZF域而非HOIL-1L的NZF域通过增强LUBAC向活化的TNFR复合物的募集，对于有效保护免受程序性细胞死亡至关重要。 SHARPIN的NZF域（而非HOIL-1L的NZF域）具有的与K63连接的泛素链的结合活性似乎与募集有关。因此，在LUBAC中NZF对泛素链的选择性识别是LUBAC功能调节的基础。

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