详细记录  
题名:Granzyme H destroys the function of critical adenoviral proteins required for viral DNA replication and granzyme B inhibition
作者:Felipe Andrade, Edward Fellows, Dieter E Jenne, Antony Rosen, C S H Young
来源:The EMBO Journal[IF=10.053] (15 Mar 2007) Article
URL :http://dx.doi.org/10.1038/sj.emboj.7601650
日期:070415
摘要: Felipe Andrade1, Edward Fellows2, Dieter E Jenne2, Antony Rosen3, 4 and C S H Young5

1 Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn, Mxico City, Mexico
2 Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Martinsried, Germany
3 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
4 Department of Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
5 Department of Microbiology, College of Physicians and Surgeons, Hammer Health Sciences Center, Columbia University, New York, NY, USA

To whom correspondence should be addressed
Felipe Andrade, Present address: Division of Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F Lord Bldg. Center Tower, Suite 6000, Room 608, Baltimore, MD 21224, USA. Tel.: +1 410 550 8665; Fax: +1 410 550 2072; E-mail: andrade@jhmi.edu

Received 25 January 2007; Accepted 22 February 2007; Published online 15 March 2007.

Abstract

Granzymes are key components of the immune response that play important roles in eliminating host cells infected by intracellular pathogens. Several granzymes are potent inducers of cell death. However, whether granzymes use additional mechanisms to exert their antipathogen activity remains elusive. Here, we show that in adenovirus-infected cells in which granzyme B (gzmB) and downstream apoptosis pathways are inhibited, granzyme H (gzmH), an orphan granzyme without known function, directly cleaves the adenovirus DNA-binding protein (DBP), a viral component absolutely required for viral DNA replication. We directly addressed the functional consequences of the cleavage of the DBP by gzmH through the generation of a virus that encodes a gzmH-resistant DBP. This virus demonstrated that gzmH directly induces an important decay in viral DNA replication. Interestingly, gzmH also cleaves the adenovirus 100K assembly protein, a major inhibitor of gzmB, and relieves gzmB inhibition. These results provide the first evidence that granzymes can mediate antiviral activity through direct cleavage of viral substrates, and further suggest that different granzymes have synergistic functions to outflank viral defenses that block host antiviral activities. Keywords: adenovirus, antiviral, cytotoxic, granzyme, NK 5ku 4.

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