Repression of SMAD3 by STAT3 and c-Ski induces conventional dendritic cell differentiation

Jeong-Hwan Yoon; Eunjin Bae; Yasuo Nagafuchi; Katsuko Sudo; Jin Soo Han; Seok Hee Park; Susumu Nakae; Tadashi Yamashita; Ji Hyeon Ju; Isao Matsumoto; Takayuki Sumida; Keiji Miyazawa; Mitsuyasu Kato; Masahiko Kuroda; In-Kyu Lee; Keishi Fujio; Mizuko Mamura

doi:10.26508/lsa.201900581

Repression of SMAD3 by STAT3 and c-Ski induces conventional dendritic cell differentiation

Life Sci Alliance. 2024 Jul 3;7(9):e201900581. doi: 10.26508/lsa.201900581. Print 2024 Sep.

Authors

Jeong-Hwan Yoon^{1

2

3

4}, Eunjin Bae^{2

5

6}, Yasuo Nagafuchi⁷, Katsuko Sudo⁸, Jin Soo Han⁴, Seok Hee Park⁹, Susumu Nakae¹⁰, Tadashi Yamashita¹¹, Ji Hyeon Ju¹², Isao Matsumoto¹³, Takayuki Sumida¹³, Keiji Miyazawa¹⁴, Mitsuyasu Kato⁶, Masahiko Kuroda², In-Kyu Lee¹, Keishi Fujio⁷, Mizuko Mamura^{15

3

16}

Affiliations

¹ Biomedical Research Institute, Kyungpook National University Hospital, Daegu, Republic of Korea.
² Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan.
³ Shin-Young Medical Institute, Chiba, Japan.
⁴ Institute for the 3Rs, Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea.
⁵ Department of Companion Health, Yeonsung University, Anyang, Republic of Korea.
⁶ Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
⁷ Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁸ Animal Research Center, Tokyo Medical University, Tokyo, Japan.
⁹ Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea.
¹⁰ Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan.
¹¹ Laboratory of Veterinary Biochemistry, Azabu University School of Veterinary Medicine, Sagamihara, Japan.
¹² Department of Rheumatology, Catholic University of Korea, Seoul St. Mary Hospital, Seoul, Republic of Korea.
¹³ Department of Internal Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁴ Departments of Biochemistry, University of Yamanashi, Yamanashi, Japan.
¹⁵ Biomedical Research Institute, Kyungpook National University Hospital, Daegu, Republic of Korea [email protected].
¹⁶ Department of Advanced Nucleic Acid Medicine, Tokyo Medical University, Tokyo, Japan.

Abstract

A pleiotropic immunoregulatory cytokine, TGF-β, signals via the receptor-regulated SMADs: SMAD2 and SMAD3, which are constitutively expressed in normal cells. Here, we show that selective repression of SMAD3 induces cDC differentiation from the CD115⁺ common DC progenitor (CDP). SMAD3 was expressed in haematopoietic cells including the macrophage DC progenitor. However, SMAD3 was specifically down-regulated in CD115⁺ CDPs, SiglecH^- pre-DCs, and cDCs, whereas SMAD2 remained constitutive. SMAD3-deficient mice showed a significant increase in cDCs, SiglecH^- pre-DCs, and CD115⁺ CDPs compared with the littermate control. SMAD3 repressed the mRNA expression of FLT3 and the cDC-related genes: IRF4 and ID2. We found that one of the SMAD transcriptional corepressors, c-SKI, cooperated with phosphorylated STAT3 at Y705 and S727 to repress the transcription of SMAD3 to induce cDC differentiation. These data indicate that STAT3 and c-Ski induce cDC differentiation by repressing SMAD3: the repressor of the cDC-related genes during the developmental stage between the macrophage DC progenitor and CD115⁺ CDP.

MeSH terms

Animals
Cell Differentiation*
DNA-Binding Proteins* / metabolism
Dendritic Cells* / cytology
Dendritic Cells* / metabolism
Inhibitor of Differentiation Protein 2 / genetics
Inhibitor of Differentiation Protein 2 / metabolism
Interferon Regulatory Factors / genetics
Interferon Regulatory Factors / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
Proto-Oncogene Proteins* / genetics
Proto-Oncogene Proteins* / metabolism
STAT3 Transcription Factor* / genetics
STAT3 Transcription Factor* / metabolism
Signal Transduction
Smad2 Protein / genetics
Smad2 Protein / metabolism
Smad3 Protein* / genetics
Smad3 Protein* / metabolism
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Flt3 protein, mouse
fms-Like Tyrosine Kinase 3
Idb2 protein, mouse
Inhibitor of Differentiation Protein 2
interferon regulatory factor-4
Interferon Regulatory Factors
Proto-Oncogene Proteins
Smad2 Protein
Smad2 protein, mouse
Smad3 Protein
Smad3 protein, mouse
Stat3 protein, mouse
STAT3 Transcription Factor
Ski protein, mouse
DNA-Binding Proteins