Xu Luo

University of Nebraska Medical Center

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Katelyn O’Neill

University of Nebraska Medical Center

Hernando López-Bertoni

Kennedy Krieger Institute

Nicholas M. George

University of Colorado Anschutz Medical Campus

Zongyi Xie

Dalian Medical University

Xiaodong Wang

National Institute of Biological Sciences, Beijing

Amarnath Natarajan

University of Nebraska Medical Center

Zipei Jiang

Wenzhou Medical University

Cai Lin

Wuhan University

Gerald M. Cohen

University of Leicester

Natalie M. Targy

University of Nebraska Medical Center

Cooperative Institutions

University of Nebraska Medical Center

Wenzhou Medical University

First Affiliated Hospital of Wenzhou Medical University

Nebraska Medical Center

Sun Yat-sen University

Chinese Academy of Sciences

National Institutes of Health

Chongqing Medical University

Chinese Academy of Medical Sciences & Peking Union Medical College

Shanghai Jiao Tong University

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Faculty Opinions recommendation of VDAC2 enables BAX to mediate apoptosis and limit tumor development.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature (2018)

Xu Luo Katelyn O’Neill

10.3410/f.734505776.793554549

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A feature-driven variability-enabled approach to adaptive service compositions

International Journal of Web and Grid Services (2023)

Chang ai Sun Zhen Wang Yanbo Han Jun Han Xu Luo

Feature (linguistics)

10.1504/ijwgs.2023.10054495

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A three-helix homo-oligomerization domain containing BH3 and BH1 is responsible for the apoptotic activity of Bax

Genes & Development (2007)

Nicholas M. George Jacquelynn J.D. Evans Xu Luo

Homo-oligomerization of Bax (or Bak) has been hypothesized to be responsible for cell death through the mitochondria-dependent apoptosis pathway. However, partly due to a lack of structural information on the Bax homo-oligomerization and apoptosis inducing domain(s), this hypothesis has remained difficult to test. In this study, we identified a three-helix unit, comprised of the BH3 (helix 2) and BH1 domains (helix 4 and helix 5), as the homo-oligomerization domain of Bax. When targeted to mitochondria, this minimum oligomerization unit induced apoptosis in Bax −/− Bak −/− mouse embryonic fibroblasts (DKO). Strikingly, the central helix of Bax (helix 5), when replacing the corresponding helix (helix 5) of Bcl-xL, an anti-apoptotic Bcl-2 family protein structurally homologous to Bax, converted Bcl-xL into a Bax-like molecule capable of forming oligomers and causing apoptosis in the DKO cells. Finally, a series of systematic mutagenesis analyses revealed that homo-oligomerization is both necessary and sufficient for the apoptotic activity of Bax. These results suggest that active Bax causes mitochondrial damage through homo-oligomers of a three-helix functional unit.

Helix (gastropod)

Bcl-2-associated X protein

10.1101/gad.1553607

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Citations (126)

Perturbation of the Bcl-2 Network and an Induced Noxa/Bcl-xL Interaction Trigger Mitochondrial Dysfunction after DNA Damage

Journal of Biological Chemistry (2010)

Hernando López-Bertoni Liqiang Zhang Nicholas M. George Xiaoqiong Liu Xiaming Pang

How most apoptotic stimuli trigger mitochondrial dysfunction remains to be resolved. We screened the entire Bcl-2 network for its involvement in DNA damage-induced apoptosis in HeLa cells. Although the anti-apoptotic member Bcl-xL served as a major suppressor, apoptosis initiated only when both Mcl-1 and Bcl-xL were eliminated. The pro-apoptotic members Bak, Bad, Bim, and Noxa were required for apoptosis induced by DNA damaging agents camptothecin and UV. We, therefore, used a His-tagged Bcl-xL expression system to capture the relevant BH3-only proteins that bind to Bcl-xL in response to DNA damage. Surprisingly, unlike Bad and Bim, which bound Bcl-xL constitutively, Noxa became "Mcl-1-free" and interacted with Bcl-xL after DNA damage but not after death receptor engagement. Similar observations were also made in A431 cells. Importantly, this induced interaction caused cytochrome c release and apoptosis and was directly inhibited by Mcl-1, a protein eliminated or inactivated after DNA damage. These results suggest that the loss/inactivation of Mcl-1 in conjunction with an induced Noxa/Bcl-xL interaction may serve as a trigger for mitochondrial dysfunction during DNA damage-induced apoptosis.

Bcl-xL

HeLa

Puma

Bcl-2 Family

10.1074/jbc.m109.086231

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Citations (55)

Comparative Transcriptome Analysis Depicts Candidate Genes Involved in Skin Color Differentiation in Red Tilapia

Pakistan Journal of Zoology (2022)

Jinzhao He Pengfei Feng Junqi Qin Yun Teng Xu Luo

The tufted deer (Elaphodus cephalophus) is a unique species in the genus Elaphodus.Currently, very little is known about its nuclear and mitochondrial genomes and their phylogenetic position within the family Cervidae.In this study, we have determined the complete sequence of the mitochondrial genome of the tufted deer, by using a long polymerase chain reaction (PCR) technique.The entire mtDNA sequence is 16,196 bp in length, which compared with previous studies is the least, containing 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and a non-coding control region (CR, D-loop).The overall base composition included 33.37 % A, 29.33 % T, 23.94 % C, and 13.36 % G.According to 13 protein-coding genes and phylogenetic analysis, Elaphodus may have a sister relationship with another deer group Muntiacus and they belong to the monophyletic genus.This study depicted mitochondrial genome characteristics for E. cephalophus and deepened the understanding of the phylogenetic relationship of Cervidae.

Candidate gene

10.17582/journal.pjz/20200326090308

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TRAIL-Mediated Apoptosis in HIV-1-Infected Macrophages Is Dependent on the Inhibition of Akt-1 Phosphorylation

The Journal of Immunology (2006)

Yunlong Huang Nathan Erdmann Hui Peng Shelley Herek John S. Davis

Abstract HIV-1 uses mononuclear phagocytes (monocytes, tissue macrophages, and dendritic cells) as a vehicle for its own dissemination and as a reservoir for continuous viral replication. The mechanism by which the host immune system clears HIV-1-infected macrophages is not understood. TRAIL may play a role in this process. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. The plasma level of TRAIL is increased in HIV-1-infected patients, particularly those with high viral loads. To study the effect of elevated TRAIL on mononuclear phagocytes, we used recombinant human (rh) TRAIL and human monocyte-derived macrophages (MDM) as an in vitro model. Our results demonstrated rhTRAIL-induced apoptosis in HIV-1-infected MDM and inhibited viral replication, while having a reduced effect on uninfected MDM. HIV-1 infection significantly decreased Akt-1 phosphorylation; rhTRAIL exposure further decreased Akt-1 phosphorylation. Infection with a dominant-negative Akt-1 adenovirus potentiated rhTRAIL-induced apoptosis, while constitutively active Akt-1 blocked rhTRAIL-induced apoptosis in HIV-1-infected MDM. From this data we conclude the death ligand TRAIL preferentially provokes apoptosis of HIV-1-infected MDM, and the mechanism is reliant upon the inhibition of Akt-1 phosphorylation. Understanding this mechanism may facilitate the elimination of HIV-1-infected macrophages and lead to new therapeutic avenues for treatment of HIV-1 infection.

10.4049/jimmunol.177.4.2304

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Citations (38)

Pivotal Role of Inosine Triphosphate Pyrophosphatase in Maintaining Genome Stability and the Prevention of Apoptosis in Human Cells

PLoS ONE (2012)

Miriam R. Menezes I.S.-R. Waisertreiger Hernando López-Bertoni Xu Luo Youri I. Pavlov

Pure nucleotide precursor pools are a prerequisite for high-fidelity DNA replication and the suppression of mutagenesis and carcinogenesis. ITPases are nucleoside triphosphate pyrophosphatases that clean the precursor pools of the non-canonical triphosphates of inosine and xanthine. The precise role of the human ITPase, encoded by the ITPA gene, is not clearly defined. ITPA is clinically important because a widespread polymorphism, 94C>A, leads to null ITPase activity in erythrocytes and is associated with an adverse reaction to thiopurine drugs. We studied the cellular function of ITPA in HeLa cells using the purine analog 6-N hydroxylaminopurine (HAP), whose triphosphate is also a substrate for ITPA. In this study, we demonstrate that ITPA knockdown sensitizes HeLa cells to HAP-induced DNA breaks and apoptosis. The HAP-induced DNA damage and cytotoxicity observed in ITPA knockdown cells are rescued by an overexpression of the yeast ITPase encoded by the HAM1 gene. We further show that ITPA knockdown results in elevated mutagenesis in response to HAP treatment. Our studies reveal the significance of ITPA in preventing base analog-induced apoptosis, DNA damage and mutagenesis in human cells. This implies that individuals with defective ITPase are predisposed to genome damage by impurities in nucleotide pools, which is drastically augmented by therapy with purine analogs. They are also at an elevated risk for degenerative diseases and cancer.

ITPA

Nucleoside triphosphate

10.1371/journal.pone.0032313

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Citations (39)

Faculty Opinions recommendation of BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature (2019)

Xu Luo Katelyn O’Neill

10.3410/f.734500725.793559109

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Bax Contains Two Functional Mitochondrial Targeting Sequences and Translocates to Mitochondria in a Conformational Change- and Homo-oligomerization-driven Process

Journal of Biological Chemistry (2009)

Nicholas M. George Natalie M. Targy Jacquelynn J.D. Evans Liqiang Zhang Xu Luo

The apoptosis gateway protein Bax normally exists in the cytosol as a globular shaped monomer composed of nine alpha-helices. During apoptosis, Bax translocates to the mitochondria, forms homo-oligomers, and subsequently induces mitochondrial damage. The mechanism of Bax mitochondrial translocation remains unclear. Among the nine alpha-helices of Bax, helices 4, 5, 6, and 9 are capable of targeting a heterologous protein to mitochondria. However, only helices 6 and 9 can independently direct the oligomerized Bax to the mitochondria. Although Bax mitochondrial translocation can still proceed with mutations in either helix 6 or helix 9, combined mutations completely abolished mitochondrial targeting in response to activating signals. Using a proline mutagenesis scanning analysis, we demonstrated that conformational changes were sufficient to cause Bax to move from the cytosol to the mitochondria. Moreover, we found that homo-oligomerization of Bax contributed to its mitochondrial translocation. These results suggest that Bax is targeted to the mitochondria through the exposure of one or both of the two functional mitochondrial targeting sequences in a conformational change-driven and homo-oligomerization-aided process.

Conformational change

Bcl-2-associated X protein

10.1074/jbc.m109.049924

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Citations (42)

Hypoxia-induced mesenchymal stem cells inhibit corneal fibroblast proliferation by regulating the WWP2/Notch1 axis

Regenerative Medicine (2022)

Chongmeng Yang Jian Pan Xu Luo Jianmin Li Zipei Jiang

Aim: This study aimed to explore the role of hypoxic mesenchymal stem cells (MSCs) in corneal alkali burns and the underlying mechanism. Materials & methods: Rat corneal fibroblasts were incubated with IL-6, followed by treatment with hypoxic MSC supernatant. A rat corneal alkali burn model was implemented and processed with hypoxic MSCs. The associated factors were detected by corresponding methods. Results: Hypoxic MSCs reduced the Notch1 level and the proliferation of rat corneal fibroblasts. Hypoxic MSCs or WWP2 overexpression in MSCs enhanced ubiquitination of Notch1. WWP2 interacted with Notch1, and WWP2 silencing reversed the effects of the hypoxic MSCs. Hypoxic MSC treatment in vivo decreased the corneal neovascularization scores and opacity scores. Conclusion: Hypoxic MSCs inhibited inflammation and alleviated corneal injury in alkali burns via the WWP2/Notch1 axis.Acute ocular chemical burns are ophthalmic emergencies which require immediate diagnosis and treatment. Quiescent corneal cells differentiate into active fibroblast and myofibroblast phenotypes after corneal injury. Mesenchymal stem cells (MSCs) under hypoxia treatment are applied for the treatment of acute ocular chemical burns. We aimed to explore the role of hypoxic MSCs in corneal alkali burns and the underlying mechanism. The result showed that hypoxic MSCs reduced the proliferation of rat corneal fibroblasts, implying an anti-inflammatory effect. In vivo, treatment with hypoxic MSCs decreased the corneal neovascularization scores and opacity scores, indicating a protective effect on corneal alkali burns. We concluded that hypoxic MSCs could alleviate corneal injury in alkali burns and may be a promising therapeutic option for corneal alkali burns.

Corneal Neovascularization

Hypoxia

Corneal inflammation

Myofibroblast

Corneal ulceration

10.2217/rme-2021-0173

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Citations (3)