Human Immunodeficiency Virus Type 1 Vpr Interacts with Antiapoptotic Mitochondrial Protein HAX-1

Yedavalli, Venkat R. K.; Shih, Hsiu‐Ming; Chiang, Yu-Ping; Lu, Chi-Jen; Chang, Luan‐Yin; Chen, Mao-Yuan; Chuang, Che-Yen; Dayton, Andrew I.; Jeang, Kuan‐Teh; Huang, Li‐Min

doi:10.1128/jvi.79.21.13735-13746.2005

Cited by 73 publications

(73 citation statements)

References 61 publications

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“…The overexpression of HAX-1 in cSCC was also confirmed at the protein level by immunohistochemistry. The HAX-1 expression was clearly up-regulated in most tumor tissue sections and the immuno-reactivity mainly in cytoplasm of the cells, which is consistent with previous findings that HAX-1 associating with cytoplasmic structures [15][16][17]. Besides that, we also found that there were significant differences in thickness, differentiation and TNM stages between high HAX-1 expression group and low HAX-1 expression group.…”

Section: Discussionsupporting

confidence: 81%

▪ Cutaneous Squamous Cell Carcinoma

Witt¹

2005

Salivary Gland Diseases

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HAX-1 is an anti-apoptotic factor and overexpressed in many types of cancers. However, the functional role of HAX-1 in human cutaneous squamous cell carcinoma (cSCC) remains unclear. Our aim was to investigate the expression of HAX-1 in cSCC and its relationship with the development of cSCC. HAX-1 expression in cSCC tissues and in-vitro cell models were evaluated by real-time quantitative PCR (RT-qPCR), Western blot and immunohistochemistry. And the RNAi strategy was used to observe the relationship of HAX-1 and cSCC in A431 cells. The mRNA and protein level of HAX-1 were significantly higher in cSCC compared with normal tissue. There were significant differences in thickness (P=0.014), differentiation (P=0.027) and TNM stages (P=0.007). After knockdown the expression of HAX-1 by siRNA, the proliferation and the motility of A431 cell was inhibited obviously, and the apoptosis of A431 cells were induced too. HAX-1 may be a risk factor for patients with cSCC. As a potential tumor promoter in cSCC, HAX-1 may be a novel potential therapeutic target for cSCC treatment and deserves further investigation.

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Section: Discussionsupporting

confidence: 81%

▪ Cutaneous Squamous Cell Carcinoma

Witt¹

2005

Salivary Gland Diseases

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“…An equivalent mechanism of antipathogen activity with continuous survival of the target cell has been described for GrH (53). Future studies should investigate such scenarios for Hax-1, which has been identified as a binding target for proteins made by different viruses, including Epstein-Barr virus, Kaposi's sarcoma associated herpes virus, and human immunodeficiency virus, type 1 (32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

“…Promotion of cell survival by Hax-1 was also elucidated in cardiomyocytes, where it functions in the regulation of calcium signaling through dynamic interactions with phospholamban and sarcoplasmic reticulum Ca-ATPase (SERCA2a) (29 -31). Hax-1 has also been elucidated as a binding target for several viral proteins encoded by Epstein-Barr virus, Kaposi's sarcoma associated herpes virus, and human immunodeficiency virus, type 1 (32)(33)(34)(35), but the biological implications of these interactions remain unclear.…”

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confidence: 99%

Deregulation of Mitochondrial Membrane Potential by Mitochondrial Insertion of Granzyme B and Direct Hax-1 Cleavage

Han

Goldstein

Hou

et al. 2010

Journal of Biological Chemistry

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The cytoplasm and the nucleus have been identified as activity sites for granzyme B (GrB) following its delivery from cytotoxic lymphocyte granules into target cells. Here we report on the ability of exogenous GrB to insert into and function within a proteinase K-resistant mitochondrial compartment. We identified Hax-1 (HS-1-associated protein X-1), a mitochondrial protein involved in the maintenance of mitochondrial membrane potential, as a GrB substrate within the mitochondrion. GrB cleaves Hax-1 into two major fragments: an N-terminal fragment that localizes to mitochondria and a C-terminal fragment that localizes to the cytosol after being released from GrBtreated mitochondria. The N-terminal Hax-1 fragment major cellular impact is on the regulation of mitochondrial polarization. Overexpression of wild-type Hax-1 or its uncleavable mutant form protects the mitochondria against GrB or valinomycin-mediated depolarization. The N-terminal Hax-1 fragment functions as a dominant negative form of Hax-1, mediating mitochondrial depolarization in a cyclophilin D-dependent manner. Thus, induced expression of the N-terminal Hax-1 fragment results in mitochondrial depolarization and subsequent lysosomal degradation of such altered mitochondria. This study is the first to demonstrate GrB activity within the mitochondrion and to identify Hax-1 cleavage as a novel mechanism for GrB-mediated mitochondrial depolarization.The granzyme family of serine proteases are pivotal mediators of apoptosis utilized by cytotoxic lymphocytes against targets such as virus-infected cells and tumor cells (1-6). Granzyme B (GrB) 3 exerts its cytotoxic effect after perforin-dependent intracellular delivery, acting in both cytosolic and nuclear compartments. The capacity of GrB to initiate a mitochondrial apoptotic cascade that features permeabilization of the mitochondrial outer membrane and release of apoptogenic proteins has been tied directly to cleavage of Bid (7-10). GrB-generated tBid activates the downstream executioners of the mitochondrial apoptotic cascade, Bax and/or Bak (11). However, mitochondria of Bid-deficient cells continue to release cytochrome c in response to GrB, suggesting the existence of an alternative mechanism(s). Our recent studies demonstrated that GrB induces a mitochondrial apoptotic cascade by cleaving Mcl-1, an antiapoptotic Bcl-2 family member that resides on the mitochondrial outer membrane in a complex with a potent proapoptotic BH3-only protein, Bim. GrB-mediated degradation of Mcl-1 releases sequestered Bim, allowing the execution of a distinct apoptotic cascade (12, 13). The mitochondrial function of BH3-only proteins, including Bid and Bim, is strictly Bax/Bak-dependent (14). Accordingly, Bax/Bak-deficient cells are relatively resistant to GrB-mediated apoptosis, but mitochondria continue to undergo significant depolarization that cannot be attributed to currently described mechanisms of GrB-mediated apoptosis (10,15,16).Mitochondrial polarization (i.e. maintenance of its inner membrane potential) is ulti...

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“…HAX-1 also interacts with pre-IL-1␣ in human chondrocytes, although the biological properties for the complex of HAX-1 and pre-IL-1␣ have not been fully elucidated (16). The HAX-1 protein appears to be expressed ubiquitously in various normal tissues and to constitute the domain that is responsible for binding to the pre-IL-1␣, HS1, cortactin, PKD2, EBNA-LP, Bcl-2, and HIV1 Vpr proteins (21)(22)(23). The fact that HAX-1 interacts with a variety of structurally unrelated proteins suggests an essential function for HAX-1 that involves intracellular signaling and shuttling of various intracellular molecules.…”

Section: Discussionmentioning

confidence: 99%

Intracellular IL-1α-binding proteins contribute to biological functions of endogenous IL-1α in systemic sclerosis fibroblasts

Kawaguchi

Nishimagi²,

Tochimoto³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The aberrant production of precursor IL-1␣ (pre-IL-1␣) in skin fibroblasts that are derived from systemic sclerosis (SSc) is associated with the induction of IL-6 and procollagen, which contributes to the fibrosis of SSc. However, little is understood about how intracellular pre-IL-1␣ regulates the expression of the other molecules in fibroblasts. We report here that pre-IL-1␣ can form a complex with IL-1␣-binding proteins that is translocated into the nuclei of fibroblasts. Immunoprecipitation that used anti-human IL-1␣ Ab and 35 S-labeled nuclear extracts of fibroblasts showed three specific bands (Ϸ31, 35, and 65 kDa). The 31-kDa molecule was identified as pre-IL-1␣, and the 35-and 65-kDa molecules might be pre-IL-1␣-binding proteins. A partial sequencing for the 10 aa from the N-terminals of the molecules showed 100% homology for HAX-1 (HS1-associated protein X-1) and IL-1 receptor type II (IL-1RII). Suppression of the genes of HAX-1 or IL-1RII induced the inhibitory effects of IL-1 signal transduction, including production of IL-6 and procollagen, by fibroblasts. In particular, pre-IL-1␣ was not translocated into the nucleus by an inhibition of HAX-1. These findings reveal that nuclear localization of pre-IL-1␣ depends on the binding to HAX-1 and that biological activities might be elicited by the binding to both HAX-1 and IL-1RII in SSc fibroblasts.IL-1 receptor type II ͉ HS1-associated protein X-1 ͉ fibrosis ͉ collagen ͉ IL-6

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Human Immunodeficiency Virus Type 1 Vpr Interacts with Antiapoptotic Mitochondrial Protein HAX-1

Cited by 73 publications

References 61 publications

▪ Cutaneous Squamous Cell Carcinoma

▪ Cutaneous Squamous Cell Carcinoma

Deregulation of Mitochondrial Membrane Potential by Mitochondrial Insertion of Granzyme B and Direct Hax-1 Cleavage

Intracellular IL-1α-binding proteins contribute to biological functions of endogenous IL-1α in systemic sclerosis fibroblasts

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