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June 2014 Conditional ablation of HMGB1 in mice


Title201406

Conditional ablation of HMGB1 in mice

B6.129P2-Hmgb1<tm1Ttg>/TtgRbrc (RBRC06240)

 

High-mobility group box 1 (HMGB1) protein is an abundant component of mammalian nuclei, and related proteins exist in all eukaryotes. HMGB family members comprise two DNA-binding domains and are considered to be structural proteins of chromatin. In addition to being expressed in the nucleus, HMGB1 exists in the cytosol and is released into the extracellular fluid from immune cells, such as monocytes or macrophages, and from cells undergoing necrosis [1].
HMGB proteins act as a ligand capable of evoking inflammatory responses. Extracellular HMGB1 associates with receptors such as Toll-like receptors, the receptor for advanced glycosylation end products, and CD24 [1]. Wang et al. identified HMGB1 as a potential late mediator of endotoxin lethality [2]. Yanai et al. found that the interaction of immunogenic nucleic acids with HMGB proteins is required for their subsequent recognition by transmembrane and cytosolic receptors to activate innate immune responses [3].
Endogenous HMGB1 is also a critical pro-autophagic protein that enhances cell survival and limits programmed apoptotic cell death [4]. A recent report showed that oxidation of HMGB1 by cellular stress promotes its localization to the cytosol and subsequent induction of autophagy [5]. Yanai et al. generated Hmgb1-floxed mice to achieve conditional inactivation of the gene and demonstrated that mice with HMGB1 ablation in myeloid cells are sensitive to endotoxin shock, which is accompanied by massive macrophage cell death [6]. Loss of HMGB1 in macrophages results in the suppression of autophagy, which is commonly induced by lipopolysaccharide stimulation or Listeria monocytogenes infection. This newly generated conditional HMGB1 knockout mouse strain provides an opportunity to identify and characterize multiple functions of HMGB1.

 

Depositor : Tadatsugu Taniguchi, Ph.D.
Department of Molecular Immunology, Institute of Industrial Science
The University of Tokyo
Strain name : B6.129P2-Hmgb1<tm1Ttg>/TtgRbrc
RBRC No. : RBRC06240
References : [1] Yanai H, Ban T, Taniguchi T. High-mobility group box family of proteins: ligand and sensor for innate immunity.  Trends Immunol.; 33(12):633-40, 2012.
[2] Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ. HMG-1 as a late mediator of endotoxin lethality in mice. Science; 285(5425):248-51, 1999
[3] Yanai H, Ban T, Wang Z, Choi MK, Kawamura T, Negishi H, Nakasato M, Lu Y, Hangai S, Koshiba R, Savitsky D, Ronfani L, Akira S, Bianchi ME, Honda K, Tamura T, Kodama T, Taniguchi T. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature; 462(7269):99-103, 2009.
[4] Deretic V. Autophagy in immunity and cell-autonomous defense against intracellular microbes. Immunol Rev.; 240(1):92-104, 2011.
[5] Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, Hoppe G, Bianchi ME, Tracey KJ, Zeh HJ 3rd, Lotze MT. Endogenous HMGB1 regulates autophagy.  J Cell Biol.; 190(5):881-92, 2010.
[6] Yanai H, Matsuda A, An J, Koshiba R, Nishio J, Negishi H, Ikushima H, Onoe T, Ohdan H, Yoshida N, Taniguchi T. Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection. Proc Natl Acad Sci U S A.; 110(51):20699-704, 2013.

 

June 2014
Contact: Shinya Ayabe, Ph.D.
Experimental Animal Division, RIKEN BioResource Center
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