Heme Oxygenase 2 Binds Myristate to Regulate Retrovirus Assembly and TLR4 Signaling

Zhu, Young; Luo, Shukun; Sabo, Yosef; Cheng, Wang; Tong, Liang; Goff, Stephen P.

doi:10.1016/j.chom.2017.01.002

Cited by 34 publications

(36 citation statements)

References 54 publications

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“…HO2 immunoprecipitation HEK293 cells were transfected to express FLAG-tagged HO2 or its variants for 24h before harvesting for immunoprecipitation assay (56). Cells were lysed in CelLytic M Cell Lysis Reagent (Sigma, C2978) on ice for 20 min with mild agitation.…”

Section: Hanson (University Of Michigan)mentioning

confidence: 99%

Heme oxygenase-2 is post-translationally regulated by heme occupancy in the catalytic site

Liu

Dumbrepatil

Fleischhacker

et al. 2020

Journal of Biological Chemistry

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Heme oxygenase-2 (HO2) and -1 (HO1) catalyze heme degradation to biliverdin, CO, and iron, forming an essential link in the heme metabolism network. Tight regulation of the cellular levels and catalytic activities of HO1 and HO2 is important for maintaining heme homeostasis. HO1 expression is transcriptionally regulated; however, HO2 expression is constitutive. How the cellular levels and activity of HO2 are regulated remains unclear. Here, we elucidate the mechanism of post-translational regulation of cellular HO2 levels by heme. We find that, under heme-deficient conditions, HO2 is destabilized and targeted for degradation, suggesting heme plays a direct role in HO2 regulation. HO2 has three heme binding sites: one at its catalytic site, and the others at its two heme regulatory motifs (HRMs). We report that, in contrast to other HRM-containing proteins, the cellular protein level and degradation rate of HO2 are independent of heme binding to the HRMs. Rather, under heme deficiency, loss of heme binding to the catalytic site destabilizes HO2. Consistently, a HO2 catalytic site variant that is unable to bind heme exhibits a constant low protein level and an enhanced protein degradation rate compared to the wild-type HO2. Finally, HO2 is degraded by the lysosome through chaperone-mediated autophagy, distinct from other HRM-containing proteins and HO1, which are degraded by the proteasome. These results reveal a novel aspect of HO2 regulation and deepen our understanding of HO2’s role in maintaining heme homeostasis, paving the way for future investigation into HO2’s pathophysiological role in heme deficiency response.

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Section: Hanson (University Of Michigan)mentioning

confidence: 99%

Heme oxygenase-2 is post-translationally regulated by heme occupancy in the catalytic site

Liu

Dumbrepatil

Fleischhacker

et al. 2020

Journal of Biological Chemistry

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“…In addition, HO-2 binds N-myristoylated TRAM, an adaptor protein for Toll-like receptor 4 (TLR4) [ 43 ], which inhibits the TRAM-dependent lipopolysaccharide(LPS)-TLR4 pathway. These findings suggest HO-2 is a novel cellular N-myristoylated protein that negatively regulates both virus replication and host inflammatory responses [ 44 ].…”

Section: Cross Talk Among the Physiological Functional Components Of mentioning

confidence: 99%

N-myristoylation: from cell biology to translational medicine

et al. 2020

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Various lipids and lipid metabolites are bound to and modify the proteins in eukaryotic cells, which are known as ‘protein lipidation’. There are four major types of the protein lipidation, i.e. myristoylation, palmitoylation, prenylation, and glycosylphosphatidylinositol anchor. N-myristoylation refers to the attachment of 14-carbon fatty acid myristates to the N-terminal glycine of proteins by N-myristoyltransferases (NMT) and affects their physiology such as plasma targeting, subcellular tracking and localization, thereby influencing the function of proteins. With more novel pathogenic N-myristoylated proteins are identified, the N-myristoylation will attract great attentions in various human diseases including infectious diseases, parasitic diseases, and cancers. In this review, we summarize the current understanding of N-myristoylation in physiological processes and discuss the hitherto implication of crosstalk between N-myristoylation and other protein modification. Furthermore, we mention several well-studied NMT inhibitors mainly in infectious diseases and cancers and generalize the relation of NMT and cancer progression by browsing the clinic database. This review also aims to highlight the further investigation into the dynamic crosstalk of N-myristoylation in physiological processes as well as the potential application of protein N-myristoylation in translational medicine.

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“…Further, ASH1L also plays a role in the suppression of TLR-mediated immune response (Xia et al, 2013). HMOX1 and HMOX2, which are known to have an antiviral effect, are downregulated (Soota and Maliakkal, 2014;Zhu et al, 2017) (Table S2). HMOX1 protects cells from programmed cell death by catabolizing free heme and its induction can have a therapeutic effect in different immune-mediated inflammatory diseases (Gozzelino et al, 2010).…”

Section: Methytranferases and Heme Catabolismmentioning

confidence: 99%

Host metabolic reprogramming in response to SARS-Cov-2 infection

Moolamalla

Chauhan

Vinod

2020

Preprint

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Understanding the pathogenesis of SARS-CoV-2 is important for developing effective treatment strategies. Viruses hijack the host metabolism to redirect the resources for their replication and survival. How SARS-CoV-2 influences the host metabolism is still unclear. In this study, we analyzed transcriptomic data obtained from different human respiratory cell lines and patient samples (Swab, PBMC, lung biopsy, BALF) to understand the metabolic alterations in response to SARS-CoV-2 infection. For this purpose, the expression pattern of metabolic genes in the human genome-scale metabolic network model Recon3D was explored. We identified metabolic genes and pathways and reporter metabolites under each SARS-CoV-2-infected condition and compared them to identify common and unique changes in the metabolism. Our analysis revealed host-dependent dysregulation of glycolysis, mitochondrial metabolism, amino acid metabolism, glutathione metabolism, polyamine synthesis, and lipid metabolism. We observed different metabolic changes that are pro- and antiviral in nature. We generated hypotheses on how antiviral metabolism can be targeted/enhanced for reducing viral titers. These warrant further exploration with more samples and in vitro studies to test predictions.

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Heme Oxygenase 2 Binds Myristate to Regulate Retrovirus Assembly and TLR4 Signaling

Cited by 34 publications

References 54 publications

Heme oxygenase-2 is post-translationally regulated by heme occupancy in the catalytic site

Heme oxygenase-2 is post-translationally regulated by heme occupancy in the catalytic site

N-myristoylation: from cell biology to translational medicine

Host metabolic reprogramming in response to SARS-Cov-2 infection

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