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@article{1419903,
author = {Serwas, N.K. and Huemer, J. and Dieckmann, R. and Mejstrikova, E. and Garncarz, W. and Litzman, Jiří and Hoeger, B. and Zapletal, O. and Janda, A. and Bennett, K.L. and Kain, R. and Kerjaschky, D. and Boztug, K.},
article_location = {LAUSANNE},
article_number = {MAR 29 2018},
doi = {http://dx.doi.org/10.3389/fimmu.2018.00588},
keywords = {primary immunodeficiency; neutrophil granulocytes; granule organization; C/EBP epsilon; specific granule deficiency},
language = {eng},
issn = {1664-3224},
journal = {Frontiers in Immunology},
title = {CEBPE-Mutant Specific Granule Deficiency Correlates With Aberrant Granule Organization and Substantial Proteome Alterations in Neutrophils},
volume = {9},
year = {2018}
}
TY - JOUR
ID - 1419903
AU - Serwas, N.K. - Huemer, J. - Dieckmann, R. - Mejstrikova, E. - Garncarz, W. - Litzman, Jiří - Hoeger, B. - Zapletal, O. - Janda, A. - Bennett, K.L. - Kain, R. - Kerjaschky, D. - Boztug, K.
PY - 2018
TI - CEBPE-Mutant Specific Granule Deficiency Correlates With Aberrant Granule Organization and Substantial Proteome Alterations in Neutrophils
JF - Frontiers in Immunology
VL - 9
IS - MAR 29 2018
SP - 1-15
EP - 1-15
PB - FRONTIERS MEDIA SA
SN - 16643224
KW - primary immunodeficiency
KW - neutrophil granulocytes
KW - granule organization
KW - C/EBP epsilon
KW - specific granule deficiency
N2 - Specific granule deficiency (SGD) is a rare disorder characterized by abnormal neutrophils evidenced by reduced granules, absence of granule proteins, and atypical bilobed nuclei. Mutations in CCAAT/enhancer-binding protein-epsilon (CEBPE) are one molecular etiology of the disease. Although C/EBP epsilon has been studied extensively, the impact of CEBPE mutations on neutrophil biology remains elusive. Here, we identified two SGD patients bearing a previously described heterozygous mutation (p.Val218Ala) in CEBPE. We took this rare opportunity to characterize SGD neutrophils in terms of granule distribution and protein content. Granules of patient neutrophils were clustered and polarized, suggesting that not only absence of specific granules but also defects affecting other granules contribute to the phenotype. Our analysis showed that remaining granules displayed mixed protein content and lacked several glycoepitopes. To further elucidate the impact of mutant CEBPE, we performed detailed proteomic analysis of SGD neutrophils. Beside an absence of several granule proteins in patient cells, we observed increased expression of members of the linker of nucleoskeleton and cytoskeleton complex (nesprin-2, vimentin, and lamin-B2), which control nuclear shape. This suggests that absence of these proteins in healthy individuals might be responsible for segmented shapes of neutrophilic nuclei. We further show that the heterozygous mutation p.Val218Ala in CEBPE causes SGD through prevention of nuclear localization of the protein product. In conclusion, we uncover that absence of nuclear C/EBP epsilon impacts on spatiotemporal expression and subsequent distribution of several granule proteins and further on expression of proteins controlling nuclear shape.
ER -
SERWAS, N.K., J. HUEMER, R. DIECKMANN, E. MEJSTRIKOVA, W. GARNCARZ, Jiří LITZMAN, B. HOEGER, O. ZAPLETAL, A. JANDA, K.L. BENNETT, R. KAIN, D. KERJASCHKY and K. BOZTUG. CEBPE-Mutant Specific Granule Deficiency Correlates With Aberrant Granule Organization and Substantial Proteome Alterations in Neutrophils. \textit{Frontiers in Immunology}. LAUSANNE: FRONTIERS MEDIA SA, 2018, vol.~9, MAR 29 2018, p.~1-15. ISSN~1664-3224. Available from: https://dx.doi.org/10.3389/fimmu.2018.00588.
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