UXT-V1 Facilitates the Formation of MAVS Antiviral Signalosome on Mitochondria

Huang, Yao‐Zeng; Liu, Heng; Ge, Rui; Zhou, Yi; Lou, Xiwen; Wang, Chen

doi:10.4049/jimmunol.1102079

Cited by 30 publications

(34 citation statements)

References 42 publications

(47 reference statements)

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“…The observation that a GnT tyrosine is critical for TBK1 regulation suggests a potential role for tyrosine regulation of IRF3 activation, although Y627 is reportedly not phosphorylated (48,49). However, RAUL, OTUD7B, Fox01, and E3 ligase regulators may be impacted by GnTs and alter the ubiquitination of TBK1, NEMO, TRAF3, IRF3/7, or NF-B required for IFN-␤ induction (34,40,44,45,54,58,61,62,65,66). These factors provide an array of potential GnT targets IFN regulation; however, the mechanism by which GnTs inhibit TBK1-directed IRF3 and NF-B activation remains to be revealed.…”

Section: Discussionmentioning

confidence: 99%

“…required for binding to MAVS and UXT-V1 as well as for the downstream recruitment of TBK1 to MAVS complexes (Fig. 3A) (36,45,61). To investigate GnT regulatory interactions, we analyzed TRAF3 domains required for binding to the GnT using C-terminal truncations of TRAF3 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The absence of direct coprecipitation of GnT-TBK1 complexes suggests several ancillary mechanisms for regulating IRF3 phosphorylation. However, the list of potential GnT targets that regulate MAVS-TRAF3-TBK1 signaling responses and impact IRF3/7 and NF-B activation is large and includes OTUD7B, Fox01, TRIAD3a, CYLD, UXT-V1, RNF11/125, Mindbomb1/2, NLRX1, SOCS1, TRIM21/ 23/28/38, ISG56, optineurin, OTUB1/2, MIP-T3, TRAF2, NIK, NLRP4, RAUL, TRIP, NLRC5, DUBA, NAP1, SINTBAD, ITCH, A20, TAX1BP, AIBIN1 and NEMO (36,39,40,44,45,54,59,(61)(62)(63) (27,40,58,(62)(63)(64). Interestingly, tyrosine phosphorylation of the E3 ubiquitin ligase TRIM21 regulates IRF3 activity and demonstrates a role for phosphotyrosine regulation of serine-phosphorylated IRF3 (62).…”

Section: Discussionmentioning

confidence: 99%

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Hantavirus GnT Elements Mediate TRAF3 Binding and Inhibit RIG-I/TBK1-Directed Beta Interferon Transcription by Blocking IRF3 Phosphorylation

Matthys

Cimica

Dalrymple

et al. 2014

J Virol

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Hantaviruses successfully replicate in primary human endothelial cells by restricting the early induction of beta interferon (IFN-␤) and interferon-stimulated genes (ISGs). Gn proteins from NY-1V, ANDV, and TULV, but not PHV, harbor elements in their 142-residue cytoplasmic tails (GnTs) that inhibit RIG-I/MAVS/TBK1-TRAF3-directed IFN-␤ induction. Here, we define GnT interactions and residues required to inhibit TRAF3-TBK1-directed IFN-␤ induction and IRF3 phosphorylation. We observed that GnTs bind TRAF3 via residues within the TRAF-N domain (residues 392 to 415) and that binding is independent of the MAVS-interactive TRAF-C domain (residues 415 to 568). We determined that GnT binding to TRAF3 is mediated by C-terminal degrons within NY-1V or ANDV GnTs and that mutations that add degrons to TULV or PHV GnTs confer TRAF3 binding. Further analysis of GnT domains revealed that TRAF3 binding is a discrete GnT function, independent of IFN regulation, and that residues 15 to 42 from the NY-1V GnT C terminus are required for inhibiting TBK1-directed IFN-␤ transcription.

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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hantavirus GnT Elements Mediate TRAF3 Binding and Inhibit RIG-I/TBK1-Directed Beta Interferon Transcription by Blocking IRF3 Phosphorylation

Matthys

Cimica

Dalrymple

et al. 2014

J Virol

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“…Both UXTV1 and UXTV2 are ubiquitous in mouse and human cell lines but UXTV1 is less abundantly expressed [Huang et al, ]. Most of the studies to date have focused on the functions of UXTV2, while UXTV1 has been implicated in TNF‐induced apoptosis [Huang et al, ]. In this study, UXTV2 was specifically identified as a novel LOX‐PP associating protein, and is subsequently referred to as UXT.…”

mentioning

confidence: 94%

UXT Is a LOX-PP Interacting Protein That Modulates Estrogen Receptor Alpha Activity in Breast Cancer Cells

et al. 2017

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The lysyl oxidase proenzyme propeptide region (LOX-PP) is a tumor suppressor protein whose mechanism of action is not completely understood. Here, the Ubiquitously expressed Transcript (UXT) was identified in a yeast two-hybrid assay with LOX-PP as bait and confirmed as a novel LOX-PP associating protein. UXT, a prefoldin-like protein, is ubiquitous in human and mouse. Since UXT modulates androgen receptor transcriptional activity in prostate cancer, we studied its role in breast cancer. Breast tumors and derived cell lines overexpressed UXT. UXT was able to associate with the estrogen receptor alpha (ER) and decrease its transcriptional activity and target gene expression. Conversely, UXT knockdown increased ER element-dependent transcriptional activity. Ectopic LOX-PP relocalized UXT to the cytoplasm and decreased its stability. UXT ubiquitination and depletion in the presence of LOX-PP was rescued by a proteasomal inhibitor. In summary, proteasome-mediated turnover of UXT upon interaction with LOX-PP releases repression of ER transcriptional activity. J. Cell. Biochem. 118: 2347-2356, 2017. © 2017 Wiley Periodicals, Inc.

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“…Besides protein methylation, multiple transcription co-regulators have been found to be involved in the activation of NF-κB target genes. For example, the ubiquitously expressed prefoldin-like chaperone UXT (also known as STAP1 and ART-27), a small chaperone-like protein, has been reported to interact with the p65 subunit of NF-κB (also known as RELA) and functions as a transcription co-activator, as well as a cytoplasmic regulator for anti-viral pathway (Huang et al, 2011(Huang et al, , 2012Sun et al, 2007). However, how UXT contributes to the activation of NF-κB target genes is still not clear.…”

Section: Introductionmentioning

confidence: 99%

The EZH1–SUZ12 complex positively regulates the transcription of NF-κB target genes through interaction with UXT

Lei

et al. 2016

Journal of Cell Science

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Unlike other members of the polycomb group protein family, EZH1 has been shown to positively associate with active transcription on a genome-wide scale. However, the underlying mechanism for this behavior still remains elusive. Here, we report that EZH1 physically interacts with UXT, a small chaperon-like transcription co-activator. UXT specifically interacts with EZH1 and SUZ12, but not EED. Similar to upon knockdown of UXT, knockdown of EZH1 or SUZ12 through RNA interference in the cell impairs the transcriptional activation of nuclear factor (NF)-κB target genes induced by TNFα. EZH1 deficiency also increases TNFα-induced cell death. Interestingly, chromatin immunoprecipitation and the following nextgeneration sequencing analysis show that H3K27 mono-, di-and tri-methylation on NF-κB target genes are not affected in EZH1-or UXT-deficient cells. EZH1 also does not affect the translocation of the p65 subunit of NF-κB (also known as RELA) from the cytosol to the nucleus. Instead, EZH1 and SUZ12 regulate the recruitment of p65 and RNA Pol II to target genes. Taken together, our study shows that EZH1 and SUZ12 act as positive regulators for NF-κB signaling and demonstrates that EZH1, SUZ12 and UXT work synergistically to regulate pathway activation in the nucleus.

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UXT-V1 Facilitates the Formation of MAVS Antiviral Signalosome on Mitochondria

Cited by 30 publications

References 42 publications

Hantavirus GnT Elements Mediate TRAF3 Binding and Inhibit RIG-I/TBK1-Directed Beta Interferon Transcription by Blocking IRF3 Phosphorylation

Hantavirus GnT Elements Mediate TRAF3 Binding and Inhibit RIG-I/TBK1-Directed Beta Interferon Transcription by Blocking IRF3 Phosphorylation

UXT Is a LOX-PP Interacting Protein That Modulates Estrogen Receptor Alpha Activity in Breast Cancer Cells

The EZH1–SUZ12 complex positively regulates the transcription of NF-κB target genes through interaction with UXT

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