ZFC3H1, a zinc finger protein, modulates IL-8 transcription by binding with celastramycin A, a potential immune suppressor

Takeshi Tomita; Katsuaki Ieguchi; Frédéric Coin; Yasuhiro Kato; Haruhisa Kikuchi; Yoshiteru Oshima; Shoichiro Kurata; Yoshiro Maru

doi:10.1371/journal.pone.0108957

ZFC3H1, a zinc finger protein, modulates IL-8 transcription by binding with celastramycin A, a potential immune suppressor

PLoS One. 2014 Sep 30;9(9):e108957. doi: 10.1371/journal.pone.0108957. eCollection 2014.

Authors

Takeshi Tomita¹, Katsuaki Ieguchi¹, Frédéric Coin, Yasuhiro Kato², Haruhisa Kikuchi², Yoshiteru Oshima², Shoichiro Kurata², Yoshiro Maru¹

Affiliations

¹ Department of Pharmacology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.
² Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

Abstract

Celastramycin A, a small molecule that inhibits the production of antibacterial peptides in an ex vivo culture system of Drosophila, suppresses the TNFα-mediated induction of IL-8 in mammalian cells. To understand its molecular mechanism, we examined Celastramycin A binding proteins and investigated their biological functions. Our screening and subsequent pull-down assay revealed ZFC3H1 (also known as CCDC131 or CSRC2), an uncharacterized zinc finger protein, as a Celastramycin A binding protein. The knockdown of ZFC3H1 reduced IL-8 expression levels in the TNFα-stimulated lung carcinoma cell line, LU99, and UV-irradiated HeLa cells. Based on reporter assay results, we concluded that ZFC3H1 participates in the transcriptional activation of IL-8. The findings of our UV-irradiation experiments implied that ZFC3H1 may indirectly interact with ERCC1 in an activated DNA repair complex. Thus, we designated ZFC3H1 as a mammalian target of Celastramycin A (mTOC).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
DNA-Binding Proteins / metabolism
Endonucleases / metabolism
Gene Expression / drug effects
Gene Expression / radiation effects
HeLa Cells
Humans
Interleukin-8 / genetics
Interleukin-8 / metabolism*
Phosphoproteins / antagonists & inhibitors
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Protein Binding
Pyrroles / chemistry
Pyrroles / metabolism
Pyrroles / pharmacology*
RNA Interference
RNA Stability
RNA, Small Interfering / metabolism
Resorcinols / chemistry
Resorcinols / metabolism
Resorcinols / pharmacology*
Signal Transduction / drug effects
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcriptional Activation / drug effects
Tumor Necrosis Factor-alpha / pharmacology
Ultraviolet Rays

Substances

DNA-Binding Proteins
Interleukin-8
Phosphoproteins
Pyrroles
RNA, Small Interfering
Resorcinols
Transcription Factors
Tumor Necrosis Factor-alpha
ZFC3H1 protein, human
celastramycin A
ERCC1 protein, human
Endonucleases

Grants and funding

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; 21117008 (Y.M.); 25870760 (K.I.); 25122716 (K.I.); 23590347 (T.T.); 21117005 (S.K.); 23710247 (H.K.); 21310134 (Y.O.); the Japan Society for the Promotion of Science; the Program for the Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) (S.K.); the Strategic International Cooperative program from Japan Science and Technology Agency (S.K.), and the Global COE program, Multidisciplinary Education and Research Center for Regenerative Medicine (MERCREM), from MEXT, Japan (K.I. and T.T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.