TY - JOUR
T1 - Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development
AU - Choi, Jin Huk
AU - Zhong, Xue
AU - Zhang, Zhao
AU - Su, Lijing
AU - McAlpine, William
AU - Misawa, Takuma
AU - Liao, Tzu Chieh
AU - Zhan, Xiaoming
AU - Russell, Jamie
AU - Ludwig, Sara
AU - Li, Xiaohong
AU - Tang, Miao
AU - Anderton, Priscilla
AU - Moresco, Eva Marie Y.
AU - Beutler, Bruce
N1 - Funding Information:
This work was supported by a grant from the National Institutes of Health (R01-AI125581) and by the Lyda Hill Foundation. J.H. Choi, X. Zhan, J. Russell, S. Ludwig, X. Li, M. Tang, P. Anderton, and B. Beutler received salary support from Pfizer.
Publisher Copyright:
© 2020 Choi et al.
PY - 2020
Y1 - 2020
N2 - In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)–induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell–independent (TI) antibody responses. The causative mutation was in Pdia6, an essential gene encoding protein disulfide isomerase A6 (PDIA6), an oxidoreductase that functions in nascent protein folding in the endoplasmic reticulum. The immune deficiency caused by the Pdia6 mutation was, with the exception of a residual T cell developmental defect, completely rescued in irradiated wild-type recipients of PDIA6-deficient bone marrow cells, both in the absence or presence of competition. The viable hypomorphic allele uncovered in these studies reveals an essential role for PDIA6 in hematopoiesis, but one extrinsic to cells of the hematopoietic lineage. We show evidence that this role is in the proper folding of Wnt3a, BAFF, IL-7, and perhaps other factors produced by the extra-hematopoietic compartment that contribute to the development and lineage commitment of hematopoietic cells.
AB - In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)–induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell–independent (TI) antibody responses. The causative mutation was in Pdia6, an essential gene encoding protein disulfide isomerase A6 (PDIA6), an oxidoreductase that functions in nascent protein folding in the endoplasmic reticulum. The immune deficiency caused by the Pdia6 mutation was, with the exception of a residual T cell developmental defect, completely rescued in irradiated wild-type recipients of PDIA6-deficient bone marrow cells, both in the absence or presence of competition. The viable hypomorphic allele uncovered in these studies reveals an essential role for PDIA6 in hematopoiesis, but one extrinsic to cells of the hematopoietic lineage. We show evidence that this role is in the proper folding of Wnt3a, BAFF, IL-7, and perhaps other factors produced by the extra-hematopoietic compartment that contribute to the development and lineage commitment of hematopoietic cells.
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U2 - 10.1084/jem.20190006
DO - 10.1084/jem.20190006
M3 - Article
C2 - 31985756
AN - SCOPUS:85078340144
SN - 0022-1007
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
M1 - e20190006
ER -