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ELANE mutant–specific activation of different UPR pathways in congenital neutropenia
Author(s) -
Nustede Rainer,
Klimiankou Maksim,
Klimenkova Olga,
Kuznetsova Inna,
Zeidler Cornelia,
Welte Karl,
Skokowa Julia
Publication year - 2016
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13823
Subject(s) - biology , unfolded protein response , myeloid , immunology , congenital neutropenia , cancer research , mutation , genetics , gene
Summary 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 ATF 6 , and the ATF 6 target genes PPP 1R15A , DDIT 3 and HSPA 5 . 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 sh RNA and transduction of ELANE p.S126L in myeloid cells led to elevated levels of ATF 6 , PPP 1R15A and HSPA 5 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 .