Functions of rhomboid family protease RHBDL2 and thrombomodulin in wound healing

Tsung Lin Cheng; Yu Ting Wu; Hung Yu Lin; Fu Chih Hsu; Shi Kai Liu; Bi Ing Chang; Wei Sheng Chen; Chao Han Lai; Guey Yueh Shi; Hua Lin Wu

doi:10.1038/jid.2011.230

Functions of rhomboid family protease RHBDL2 and thrombomodulin in wound healing

Tsung Lin Cheng, Yu Ting Wu, Hung Yu Lin, Fu Chih Hsu, Shi Kai Liu, Bi Ing Chang, Wei Sheng Chen, Chao Han Lai, Guey Yueh Shi, Hua Lin Wu

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51 Citations (Scopus)

Abstract

The expression of thrombomodulin (TM), a membrane glycoprotein, is upregulated in neoepidermis during cutaneous wound healing. Rhomboid-like-2 (RHBDL2), an intramembrane serine protease, specifically cleaves TM at the transmembrane domain and causes the release of soluble TM (sTM). However, the physiological functions of TM and RHBDL2 in wound healing remain unclear. We demonstrated that both TM and RHBDL2 are upregulated in HaCaT cells stimulated by scratch wounds; furthermore, increased sTM was found in culture medium. Conversely, inhibition of RHBDL2 by 3,4-dichloroisocoumarin (DCI) or short hairpin RNA significantly inhibited wound-induced TM ectodomain shedding and wound healing. Both conditioned media from multiple-scratch-wounded HaCaT and recombinant sTM accelerated wound healing in HaCaT cells; such effects were abrogated by anti-TM antibodies. The RNA released from injured cells is involved in the induction of TM and RHBDL2. RHBDL2 and sTM were upregulated in ex vivo tissue culture of the injured skin. Furthermore, DCI inhibited sTM production and wound healing; this was reversed by recombinant sTM in mice. Thus, RHBDL2 and TM have important roles in wound healing via the release of sTM from keratinocytes; this may function as an autocrine/paracrine signal promoting wound healing.

Original language	English
Pages (from-to)	2486-2494
Number of pages	9
Journal	Journal of Investigative Dermatology
Volume	131
Issue number	12
DOIs	https://doi.org/10.1038/jid.2011.230
Publication status	Published - 2011 Dec

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Biology
Dermatology
Cell Biology

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10.1038/jid.2011.230

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@article{313db28c1da34f36aa8bbe5add602e8c,

title = "Functions of rhomboid family protease RHBDL2 and thrombomodulin in wound healing",

abstract = "The expression of thrombomodulin (TM), a membrane glycoprotein, is upregulated in neoepidermis during cutaneous wound healing. Rhomboid-like-2 (RHBDL2), an intramembrane serine protease, specifically cleaves TM at the transmembrane domain and causes the release of soluble TM (sTM). However, the physiological functions of TM and RHBDL2 in wound healing remain unclear. We demonstrated that both TM and RHBDL2 are upregulated in HaCaT cells stimulated by scratch wounds; furthermore, increased sTM was found in culture medium. Conversely, inhibition of RHBDL2 by 3,4-dichloroisocoumarin (DCI) or short hairpin RNA significantly inhibited wound-induced TM ectodomain shedding and wound healing. Both conditioned media from multiple-scratch-wounded HaCaT and recombinant sTM accelerated wound healing in HaCaT cells; such effects were abrogated by anti-TM antibodies. The RNA released from injured cells is involved in the induction of TM and RHBDL2. RHBDL2 and sTM were upregulated in ex vivo tissue culture of the injured skin. Furthermore, DCI inhibited sTM production and wound healing; this was reversed by recombinant sTM in mice. Thus, RHBDL2 and TM have important roles in wound healing via the release of sTM from keratinocytes; this may function as an autocrine/paracrine signal promoting wound healing.",

author = "Cheng, {Tsung Lin} and Wu, {Yu Ting} and Lin, {Hung Yu} and Hsu, {Fu Chih} and Liu, {Shi Kai} and Chang, {Bi Ing} and Chen, {Wei Sheng} and Lai, {Chao Han} and Shi, {Guey Yueh} and Wu, {Hua Lin}",

note = "Funding Information: This work was supported by a grant from the National Science Council, Executive Yuan, Taiwan (NSC98-2752-B-006-002-PAE to H.-L. Wu). ",

year = "2011",

month = dec,

doi = "10.1038/jid.2011.230",

language = "English",

volume = "131",

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T1 - Functions of rhomboid family protease RHBDL2 and thrombomodulin in wound healing

AU - Cheng, Tsung Lin

AU - Wu, Yu Ting

AU - Lin, Hung Yu

AU - Hsu, Fu Chih

AU - Liu, Shi Kai

AU - Chang, Bi Ing

AU - Chen, Wei Sheng

AU - Lai, Chao Han

AU - Shi, Guey Yueh

AU - Wu, Hua Lin

N1 - Funding Information: This work was supported by a grant from the National Science Council, Executive Yuan, Taiwan (NSC98-2752-B-006-002-PAE to H.-L. Wu).

PY - 2011/12

Y1 - 2011/12

N2 - The expression of thrombomodulin (TM), a membrane glycoprotein, is upregulated in neoepidermis during cutaneous wound healing. Rhomboid-like-2 (RHBDL2), an intramembrane serine protease, specifically cleaves TM at the transmembrane domain and causes the release of soluble TM (sTM). However, the physiological functions of TM and RHBDL2 in wound healing remain unclear. We demonstrated that both TM and RHBDL2 are upregulated in HaCaT cells stimulated by scratch wounds; furthermore, increased sTM was found in culture medium. Conversely, inhibition of RHBDL2 by 3,4-dichloroisocoumarin (DCI) or short hairpin RNA significantly inhibited wound-induced TM ectodomain shedding and wound healing. Both conditioned media from multiple-scratch-wounded HaCaT and recombinant sTM accelerated wound healing in HaCaT cells; such effects were abrogated by anti-TM antibodies. The RNA released from injured cells is involved in the induction of TM and RHBDL2. RHBDL2 and sTM were upregulated in ex vivo tissue culture of the injured skin. Furthermore, DCI inhibited sTM production and wound healing; this was reversed by recombinant sTM in mice. Thus, RHBDL2 and TM have important roles in wound healing via the release of sTM from keratinocytes; this may function as an autocrine/paracrine signal promoting wound healing.

AB - The expression of thrombomodulin (TM), a membrane glycoprotein, is upregulated in neoepidermis during cutaneous wound healing. Rhomboid-like-2 (RHBDL2), an intramembrane serine protease, specifically cleaves TM at the transmembrane domain and causes the release of soluble TM (sTM). However, the physiological functions of TM and RHBDL2 in wound healing remain unclear. We demonstrated that both TM and RHBDL2 are upregulated in HaCaT cells stimulated by scratch wounds; furthermore, increased sTM was found in culture medium. Conversely, inhibition of RHBDL2 by 3,4-dichloroisocoumarin (DCI) or short hairpin RNA significantly inhibited wound-induced TM ectodomain shedding and wound healing. Both conditioned media from multiple-scratch-wounded HaCaT and recombinant sTM accelerated wound healing in HaCaT cells; such effects were abrogated by anti-TM antibodies. The RNA released from injured cells is involved in the induction of TM and RHBDL2. RHBDL2 and sTM were upregulated in ex vivo tissue culture of the injured skin. Furthermore, DCI inhibited sTM production and wound healing; this was reversed by recombinant sTM in mice. Thus, RHBDL2 and TM have important roles in wound healing via the release of sTM from keratinocytes; this may function as an autocrine/paracrine signal promoting wound healing.

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ER -

Functions of rhomboid family protease RHBDL2 and thrombomodulin in wound healing

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