ELANE mutant–specific activation of different UPR pathways in congenital neutropenia
ELANE mutant–specific activation of different UPR pathways in congenital neutropenia
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先天性中性粒细胞减少症中不同 UPR 途径的 ELANE 突变体特异性激活
DOI：
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发表时间：
2016
影响因子：
6.5
通讯作者：
J. Skokowa
中科院分区：
文献类型：
--
作者：
R. Nustede;M. Klimiankou;O. Klimenkova;Inna S. Kuznetsova;C. Zeidler;K. Welte;J. Skokowa
许多研究已经证明了在具有编码中性粒细胞弹性蛋白酶的ELANE突变的重度先天性中性粒细胞减少症（CN）患者中诱导未折叠蛋白应答（UPR）。为什么UPR在携带相同ELANE突变的周期性中性粒细胞减少症（CyN）患者中不被激活尚不清楚。我们评估了ELANE突变体对CN和CyN患者骨髓细胞中UPR诱导的影响，并分析了额外的CN特异性缺陷是否有助于携带相同ELANE突变的CN和CyN患者之间UPR诱导的差异。我们研究了CN特异性p.C71R和p.V174_C181del（NP_001963.1）和CN/CyN共享的p.S126L（NP_001963.1）ELANE突变体。我们发现，用p.C71R转导造血细胞，而不是用p.V174_C181del或p.S126L ELANE突变体转导，诱导了ATF 6和ATF 6靶基因PPP 1 R15 A、DDIT 3和HSPA 5的表达。最近，我们发现，分泌性白细胞蛋白酶抑制剂（SLPI），一种天然的ELANE抑制剂，在CN患者的骨髓细胞中减少，但CyN患者没有。在骨髓细胞中通过shRNA敲低SLPI和转导ELANE p.S126L导致ATF 6、PPP 1 R15 A和HSPA 5 RNA水平升高，表明CyN患者中SLPI的正常水平可能保护他们免受突变ELANE诱导的UPR。总之，不同的ELANE突变体对UPR活化具有不同的影响，SLPI调节ELANE触发的UPR的程度。
A number of studies have demonstrated induction of the unfolded protein response (UPR) in patients with severe congenital neutropenia (CN) harbouring mutations of ELANE, encoding neutrophil elastase. Why UPR is not activated in patients with cyclic neutropenia (CyN) carrying the same ELANE mutations is unclear. We evaluated the effects of ELANE mutants on UPR induction in myeloid cells from CN and CyN patients, and analysed whether additional CN‐specific defects contribute to the differences in UPR induction between CN and CyN patients harbouring identical ELANE mutations. We investigated CN‐specific p.C71R and p.V174_C181del (NP_001963.1) and CN/CyN‐shared p.S126L (NP_001963.1) ELANE mutants. We found that transduction of haematopoietic cells with p.C71R, but not with p.V174_C181del or p.S126L ELANE mutants induced expression of ATF6, and the ATF6 target genes PPP1R15A, DDIT3 and HSPA5. Recently, we found that levels of secretory leucocyte protease inhibitor (SLPI), a natural ELANE inhibitor, are diminished in myeloid cells from CN patients, but not CyN patients. Combined knockdown of SLPI by shRNA and transduction of ELANE p.S126L in myeloid cells led to elevated levels of ATF6, PPP1R15A and HSPA5 RNA, suggesting that normal levels of SLPI in CyN patients might protect them from the UPR induced by mutant ELANE. In summary, different ELANE mutants have different effects on UPR activation, and SLPI regulates the extent of ELANE‐triggered UPR.
DOI：
10.1172/jci16886
发表时间：
2002-11
期刊：
The Journal of clinical investigation
影响因子：
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作者：
R. Kaufman
通讯作者：
R. Kaufman
影响因子：
20.3
作者：
Massullo, P;Druhan, LJ;Avalos, BR
通讯作者：
Avalos, BR