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Non-enzymatic role of SOD1 in intestinal stem cell growth
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Journal Article
Non-enzymatic role of SOD1 in intestinal stem cell growth
2022
Overview
Superoxide dismutase 1 (SOD1) modulates intestinal barrier integrity and intestinal homeostasis as an antioxidant enzyme. Intestinal homeostasis is maintained by the intestinal stem cells (ISCs). However, whether and how SOD1 regulates ISCs is unknown. In this study, we established intestinal organoids from tamoxifen–inducible intestinal epithelial cell–specific
Sod1
knockout (
Sod1
f/f
; Vil-creERT2
) mice. We found that loss of
Sod1
in organoids suppressed the proliferation and survival of cells and
Lgr5
gene expression. SOD1 is known for nearly half a century for its canonical role as an antioxidant enzyme. We identified its enzyme-independent function in ISC: inhibition of SOD1 enzymatic activity had no impact on organoid growth, and enzymatically inactive
Sod1
mutants could completely rescue the growth defects of
Sod1
deficient organoids, suggesting that SOD1-mediated ISC growth is independent of its enzymatic activity. Moreover,
Sod1
deficiency did not affect the ROS levels of the organoid, but induced the elevated WNT signaling and excessive Paneth cell differentiation, which mediates the occurrence of growth defects in
Sod1
deficient organoids. In vivo, epithelial
Sod1
loss induced a higher incidence of apoptosis in the stem cell regions and increased Paneth cell numbers, accompanied by enhanced expression of EGFR ligand Epiregulin (EREG) in the stromal tissue, which may compensate for
Sod1
loss and maintain intestinal structure in vivo. Totally, our results show a novel enzyme-independent function of SOD1 in ISC growth under homeostasis.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/106
/ 13/109
/ 13/51
/ 14/19
/ 14/34
/ 45/91
/ 64/60
/ Animals
/ Biomedical and Life Sciences
/ Enzymes
/ Intestinal Mucosa - metabolism
/ Intestinal Neoplasms - metabolism
/ Ligands
/ Mice
/ Reactive Oxygen Species - metabolism
/ Superoxide Dismutase - genetics
/ Superoxide Dismutase - metabolism
/ Superoxide Dismutase-1 - genetics
