Inhibition of Fam114A1 protects melanocytes from apoptosis through higher RACK1 expression

Zhou, Mi; Lin, Fuquan; Wu, Xiaochang; Ping, Zhuyi; Xu, Wen; Jin, Rong; Xu, Aie

doi:10.18632/aging.203712

Cited by 4 publications

(4 citation statements)

References 53 publications

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“…Apoptosis is a type of cell death that depends on genetically coded signals or activity within dying cells. It is concerned with the growth and development of organs and tissues, immunity, metabolism and the removal of abnormal cells [ 34 , 35 ]. Furthermore, we observed that more cellular debris at the bottom of the medium, and “drawing” of the cells morphologically under the microscope after MH treatment, and the number of AML12 cells was reduced in a time-dependent manner after MH treatment.…”

Section: Discussionmentioning

confidence: 99%

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

et al. 2022

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The body needs to generate heat to ensure basic life activities when exposed to cold temperatures. The liver, as the largest glycogen storage organ in the body and main heat-producing organ at rest, may play a role in chronic cold exposure. Recent studies suggested that pyroptosis plays a crucial role in liver diseases. However, the role of pyroptosis in cold stress-induced liver injury is not clear. Hence, in this study, we attempted to investigate the effects of chronic cold exposure on liver function, apoptosis, oxidative stress and inflammation in mice by establishing a mouse model of chronic cold exposure, and to investigate whether pyroptosis pathways are involved in the process of chronic cold exposure. In vivo, our results show that inflammatory cell infiltration and other pathological changes in liver cells and the activity of liver enzyme evidently increased in the serum and liver of cold-exposed mice, suggesting cold stress may result in liver injury. Remarkably, increased expression of heat shock protein 70 (HSP70) and HSP90 proteins proved the cold stress model is successfully constructed. Then, elevated levels of apoptosis, inflammation, oxidative stress and pyroptosis related proteins and mRNAs, such as cysteinyl aspartate specific proteinase-3 (Caspase-3), inducible nitric oxide synthase (iNOS), nuclear factor erythroid2-related factor 2 (Nrf2) and gasdermins D (GSDMD), confirmed that cold exposure activated apoptosis, oxidative stress and pyroptosis, and released inflammation cytokines. Meanwhile, in vitro, we got similar results as in vivo. Further, adding an NLR family pyrin domain containing 3 (NLRP3) inhibitors found that suppression expression of NLRP3 results in the essential proteins of pyroptosis and antioxidant evidently reduced, and adding GSDMD inhibitor found that suppression expression of GSDMD accompanies with the level of Nrf2 and heme oxygenase-1 (HO-1) obviously reduced. In summary, these findings provide a new understanding of the underlying mechanisms of the cold stress response, which can inform the development of new strategies to combat the effects of hypothermia.

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Section: Discussionmentioning

confidence: 99%

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

et al. 2022

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“…When we explored previous studies on FAM114A1 to understand its function, particularly under hypoxia, we found that apart from its role in neuronal cell development [ 13 ], melanocyte apoptosis [ 32 ] and an association with ankylosing spondylitis [ 33 ], there was very little known about this gene or its homologue FAM114A2 . A recent study in Fam114a1 −/− mice showed that cardiac function was markedly restored in the knockout mice, in angiotensin II infusion model of hypertension, when compared to the controls [ 29 ], indicating its role in oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

A Boolean approach for novel hypoxia-related gene discovery

2022

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Hypoxia plays a major role in the etiology and pathogenesis of most of the leading causes of morbidity and mortality, whether cardiovascular diseases, cancer, respiratory diseases or stroke. Despite active research on hypoxia-signaling pathways, the understanding of regulatory mechanisms, especially in specific tissues, still remain elusive. With the accessibility of thousands of potentially diverse genomic datasets, computational methods are utilized to generate new hypotheses. Here we utilized Boolean implication relationship, a powerful method to probe symmetrically and asymmetrically related genes, to identify novel hypoxia related genes. We used a well-known hypoxia-responsive gene, VEGFA, with very large human expression datasets (n = 25,955) to identify novel hypoxia-responsive candidate gene/s. Further, we utilized in-vitro analysis using human endothelial cells exposed to 1% O2 environment for 2, 8, 24 and 48 hours to validate top candidate genes. Out of the top candidate genes (n = 19), 84% genes were previously reported as hypoxia related, validating our results. However, we identified FAM114A1 as a novel candidate gene significantly upregulated in the endothelial cells at 8, 24 and 48 hours of 1% O2 environment. Additional evidence, particularly the localization of intronic miRNA and numerous HREs further support and strengthen our finding. Current results on FAM114A1 provide an example demonstrating the utility of powerful computational methods, like Boolean implications, in playing a major role in hypothesis building and discovery.

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“…RACK1 is a highly conserved tryptophan-aspartate repeat (WD-repeat) protein and is currently recognized as a multifunctional scaffold protein that is involved in a wide range of biological processes, such as viral infection [ 17 ], cell migration [ 18 ], and apoptosis [ 19 ]. It has been reported that RACK1 participates in NLRP3 inflammasome activation by promoting NLRP3 conformational changes and inflammasome assembly [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

RACK1 mediates NLRP3 inflammasome activation during Pasteurella multocida infection

Ran,

Yin,

et al. 2023

Vet Res

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Pasteurella multocida is a gram-negative bacterium that causes serious diseases in a wide range of animal species. Inflammasomes are intracellular multimolecular protein complexes that play a critical role in host defence against microbial infection. Our previous study showed that bovine P. multocida type A (PmCQ2) infection induces NLRP3 inflammasome activation. However, the exact mechanism underlying PmCQ2-induced NLRP3 inflammasome activation is not clear. Here, we show that NLRP3 inflammasome activation is positively regulated by a scaffold protein called receptor for activated C kinase 1 (RACK1). This study shows that RACK1 expression was downregulated by PmCQ2 infection in primary mouse peritoneal macrophages and mouse tissues, and overexpression of RACK1 prevented PmCQ2-induced cell death and reduced the numbers of adherent and invasive PmCQ2, indicating a modulatory role of RACK1 in the cell death that is induced by P. multocida infection. Next, RACK1 knockdown by siRNA significantly attenuated PmCQ2-induced NLRP3 inflammasome activation, which was accompanied by a reduction in the protein expression of interleukin (IL)-1β, pro-IL-1β, caspase-1 and NLRP3 as well as the formation of ASC specks, while RACK1 overexpression by pcDNA3.1-RACK1 plasmid transfection significantly promoted PmCQ2-induced NLRP3 inflammasome activation; these results showed that RACK1 is essential for NLRP3 inflammasome activation. Furthermore, RACK1 knockdown decreased PmCQ2-induced NF-κB activation, but RACK1 overexpression had the opposite effect. In addition, the immunofluorescence staining and immunoprecipitation results showed that RACK1 colocalized with NLRP3 and that NEK7 and interacted with these proteins. However, inhibition of potassium efflux significantly attenuated the RACK1-NLRP3-NEK7 interaction. Our study demonstrated that RACK1 plays an important role in promoting NLRP3 inflammasome activation by regulating NF-κB and promoting NLRP3 inflammasome assembly.

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Inhibition of Fam114A1 protects melanocytes from apoptosis through higher RACK1 expression

Cited by 4 publications

References 53 publications

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

A Boolean approach for novel hypoxia-related gene discovery

RACK1 mediates NLRP3 inflammasome activation during Pasteurella multocida infection

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