title: ELANE mutant-specific activation of different UPR pathways in congenital neutropenia.
abstract: 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.
authors.affiliation: Department of Molecular Haematopoiesis, Hannover Medical School, Hannover, Germany.|Department of Surgery, Childrens Hospital, Hannover Medical School, Hannover, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Nustede
authors.affiliation: Department of Haematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Maksim
authors.initials: M
authors.lastname: Klimiankou
authors.affiliation: Department of Molecular Haematopoiesis, Hannover Medical School, Hannover, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Klimenkova
authors.affiliation: Department of Molecular Haematopoiesis, Hannover Medical School, Hannover, Germany.
authors.forename: Inna
authors.initials: I
authors.lastname: Kuznetsova
authors.affiliation: Department of Molecular Haematopoiesis, Hannover Medical School, Hannover, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.affiliation: Department of Molecular Haematopoiesis, Hannover Medical School, Hannover, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.affiliation: Department of Haematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis; D051702:Activating Transcription Factor 6 / Q000096:biosynthesis; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D016022:Case-Control Studies; D000080984:Congenital Bone Marrow Failure Syndromes; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D019272:Leukocyte Elastase / Q000235:genetics*; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics*; D019892:eIF-2 Kinase / Q000096:biosynthesis
chemical_list: C497109:ATF4 protein, human; C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D012333:RNA, Messenger; D051701:Activating Transcription Factor 4; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D019272:Leukocyte Elastase
keywords: congenital neutropenia; unfolded protein response (UPR)