GdX/UBL4A null mice exhibit mild kyphosis and scoliosis accompanied by dysregulation of osteoblastogenesis and chondrogenesis

Ji, Liang; Li, Jun; Fu, Yanhong; Ren, Fei; Xu, Jiake; Zhou, Mengyu; Li, Peiyu; Feng, Haotian; Wang, Yinyin

doi:10.1002/cbf.3324

Cited by 16 publications

(11 citation statements)

References 20 publications

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“…Ubl4A is a multifunctional protein that is involved in diverse cellular events, from translocation of newly synthesized proteins to the ER, DNA damage repair, bone modeling, inflammatory and innate immune response, to anti-tumorigenesis [40][41][42][43][44][45][46][47][48]. Here, we showed that under nutrient starvation conditions, Ubl4A functions as a survival factor mainly by regulating the mitochondrial fusion process.…”

Section: Discussionmentioning

confidence: 96%

“…Although it belongs to the ubiquitin-like family, Ubl4A has no ubiquitination activity [39]. Instead, this protein has diverse functions, from chaperoning nascent synthesized proteins to the ER, promoting anti-tumorigenesis, potentiating autoimmune diseases, to augmenting innate immune response through NFκB signaling pathway [40][41][42][43][44][45][46][47][48]. We have shown that Ubl4A can directly interact with the Arp2/3 complex to promote actin branching [49].…”

Section: Introductionmentioning

confidence: 99%

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Ubl4A is critical for mitochondrial fusion process under nutrient deprivation stress

et al. 2020

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Mitochondrial fusion and fission are dynamic processes regulated by the cellular microenvironment. Under nutrient starvation conditions, mitochondrial fusion is strengthened for energy conservation. We have previously shown that newborns of Ubl4A-deficient mice were more sensitive to starvation stress with a higher rate of mortality than their wild-type littermates. Ubl4A binds with the actin-related protein Arp2/3 complex to synergize the actin branching process. Here, we showed that deficiency in Ubl4A resulted in mitochondrial fragmentation and apoptosis. A defect in the fusion process was the main cause of the mitochondrial fragmentation and resulted from a shortage of primed Arp2/3 complex pool around the mitochondria in the Ubl4A-deficient cells compared to the wild-type cells. As a result, the mitochondrial fusion process was not undertaken quickly enough to sustain starvation stress-induced cell death. Consequently, fragmented mitochondria lost their membrane integrity and ROS was accumulated to trigger caspase 9-dependent apoptosis before autophagic rescue. Furthermore, the wild-type Ubl4A, but not the Arp2/3-binding deficient mutant, could rescue the starvation-induced mitochondrial fragmentation phenotype. These results suggest that Ubl4A promotes the mitochondrial fusion process via Arp2/3 complex during the initial response to nutrient deprivation for cell survival.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Ubl4A is critical for mitochondrial fusion process under nutrient deprivation stress

et al. 2020

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“…GdX also promotes Akt activation through interacting with actin related protein 2/3 (Arp2/3) in the cytoplasm 21. While studying the regulation of signal transducer and activator of transcription factor 3 (STAT3), we discovered GdX mediates tyrosine phosphatase TC45 recruitment for STAT3 dephosphorylation 17 and regulates osteoblastogenesis and chondrogenesis 22. Interestingly, in this study, we found that GdX-deficient mice 23 were resistant to lipopolysaccharides (LPS)-induced endotoxin shock and dextran sulfate sodium (DSS)-induced colitis, suggesting a critical effect of GdX in NF-κB signaling pathway modulation.…”

Section: Introductionmentioning

confidence: 99%

Absence of GdX/UBL4A Protects against Inflammatory Diseases by Regulating NF-кB Signaling in Macrophages and Dendritic Cells

Liu¹,

Zhou²,

Li³

et al. 2019

Theranostics

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Nuclear factor-kappa B (NF-κB) activation is critical for innate immune responses. However, cellular-intrinsic regulation of NF-κB activity during inflammatory diseases remains incompletely understood. Ubiquitin-like protein 4A (UBL4A, GdX) is a small adaptor protein involved in protein folding, biogenesis and transcription. Yet, whether GdX has a role during innate immune response is largely unknown. Methods: To investigate the involvement of GdX in innate immunity, we challenged GdX-deficient mice with lipopolysaccharides (LPS). To investigate the underlying mechanism, we performed RNA sequencing, real-time PCR, ELISA, luciferase reporter assay, immunoprecipitation and immunoblot analyses, flow cytometry, and structure analyses. To investigate whether GdX functions in inflammatory bowel disease, we generated dendritic cell (DC), macrophage (Mφ), epithelial-cell specific GdX-deficient mice and induced colitis with dextran sulfate sodium. Results: GdX enhances DC and Mφ-mediated innate immune defenses by positively regulating NF-κB signaling. GdX-deficient mice were resistant to LPS-induced endotoxin shock and DSS-induced colitis. DC- or Mφ- specific GdX-deficient mice displayed alleviated mucosal inflammation. The production of pro-inflammatory cytokines by GdX-deficient DCs and Mφ was reduced. Mechanistically, we found that tyrosine-protein phosphatase non-receptor type 2 (PTPN2, TC45) and protein phosphatase 2A (PP2A) form a complex with RelA (p65) to mediate its dephosphorylation whereas GdX interrupts the TC45/PP2A/p65 complex formation and restrict p65 dephosphorylation by trapping TC45. Conclusion: Our study provides a mechanism by which NF-κB signaling is positively regulated by an adaptor protein GdX in DC or Mφ to maintain the innate immune response. Targeting GdX could be a strategy to reduce over-activated immune response in inflammatory diseases.

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“…The results suggest that UBL4A may function as a tumor suppressor, further implied when the deletion of UBL4A facilitated MEF cell proliferation, potentially providing a new strategy for tumor therapy. Liang et al (2018) recently identified UBL4A as being a novel regulator in bone development. GdX is the UBL4A gene; GdX knockout mice indicate a critical role of UBL4A in skeletal biology; at the embryonic stage they have decreased bone mineral density, and later demonstrate a blended spine and reduced growth.…”

Section: Disease Seemingly Unrelated To the Chaperone Systemmentioning

confidence: 99%

The roles of cytosolic quality control proteins, SGTA and the BAG6 complex, in disease

Benarroch

Austin

Ahmed

et al. 2019

Molecular Chaperones in Human Disorders

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GdX/UBL4A null mice exhibit mild kyphosis and scoliosis accompanied by dysregulation of osteoblastogenesis and chondrogenesis

Cited by 16 publications

References 20 publications

Ubl4A is critical for mitochondrial fusion process under nutrient deprivation stress

Ubl4A is critical for mitochondrial fusion process under nutrient deprivation stress

Absence of GdX/UBL4A Protects against Inflammatory Diseases by Regulating NF-кB Signaling in Macrophages and Dendritic Cells

The roles of cytosolic quality control proteins, SGTA and the BAG6 complex, in disease

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