DAXX represents a new type of protein-folding enabler

Huang, Liangqian; Agrawal, Trisha; Zhu, Guixin; Yu, Sixiang; Tao, Liming; Lin, Jia Bei; Marmorstein, Ronen; Shorter, James; Yang, Xiaolu

doi:10.1038/s41586-021-03824-5

Cited by 58 publications

(64 citation statements)

References 39 publications

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“…DAXX was recently described as a protein chaperone able to solubilize protein aggregates and unfold misfolded proteins 52 . We investigated whether this activity was required for SARS-CoV-2 restriction using a DAXX mutant lacking the D/E domain, critical for this chaperone activity 52 . The DAXXΔD/E mutant, while expressed at similar levels than WT DAXX in transfected cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen

et al. 2022

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Interferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identify DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 and SARS-CoV replication in human cells. Basal expression of DAXX is sufficient to limit the replication of SARS-CoV-2, and DAXX over-expression further restricts infection. DAXX restricts an early, post-entry step of the SARS-CoV-2 life cycle. DAXX-mediated restriction of SARS-CoV-2 is independent of the SUMOylation pathway but dependent on its D/E domain, also necessary for its protein-folding activity. SARS-CoV-2 infection triggers the re-localization of DAXX to cytoplasmic sites and promotes its degradation. Mechanistically, this process is mediated by the viral papain-like protease (PLpro) and the proteasome. Together, these results demonstrate that DAXX restricts SARS-CoV-2, which in turn has evolved a mechanism to counteract its action.

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Section: Resultsmentioning

confidence: 99%

“…Both mutants were described in. 48 DAXX∆D/E is lacking its 414-505 domain and has been described in 52 b , c SUMOylation-deficient DAXX mutants are still able to restrict SARS-CoV-2. 293T-ACE2 cells were transfected with HA-DAXX WT; HA-DAXX 15KR; HA-DAXX∆SIM; or with HA-NBR1 as negative control plasmid.…”

Section: Resultsmentioning

confidence: 99%

Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen

et al. 2022

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“…Importantly, although SUMO/SIM interactions might play an important role to mediate HIRA accumulation in PML NBs, our study unveils the availability of H3.3 within PML NBs as a novel important parameter controlling this accumulation. DAXX is essential for the correct folding of H3.3-H4 dimers (76) as well as other proteins as shown recently (77). Knockdown of DAXX leads to destabilization of both the DAXX chaperone and the H3.3-H4 dimers, and it prevents localization of neosynthesized H3.3-H4 dimers in PML NBs in primary cells (30,31,76).…”

Section: Hira Accumulation In Pml Nbs Depends On the Availability Of An H33-h4 Pool And On Transcriptional Activitymentioning

confidence: 83%

Interplay between PML NBs and HIRA for H3.3 dynamics following type I interferon stimulus

Kleijwegt

Bressac

Cohen³

et al. 2021

Preprint

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Promyelocytic Leukemia Nuclear Bodies (PML NBs) are nuclear membrane-less organelles physically associated with chromatin underscoring their crucial role in genome function. The H3.3 histone chaperone complex HIRA accumulates in PML NBs upon senescence, viral infection or IFN-I treatment in primary cells. Yet, the molecular mechanisms of this partitioning and its function in regulating histone dynamics have remained elusive. Here, by using specific siRNAs and protein Affimers, we identify intermolecular SUMO-SIM interactions as an essential mechanism for HIRA recruitment in PML NBs. In addition, we demonstrate that HIRA localization in the nuclear bodies is intimately linked to the presence of a soluble pool of H3.3-H4 dimers inside PML NBs, that is not found in cancer cells. Transcription inhibition prevents HIRA accumulation in PML NBs underscoring the importance of transcriptional activity to drive HIRA through PML NBs. Finally, in the context of inflammatory responses, HIRA and PML are necessary for the prolonged H3.3 deposition at the transcriptional end sites of interferon-stimulated genes (ISGs), well beyond the peak of transcription. We thus propose that HIRA partitioning in PML NBs is essential to regulate H3.3 deposition on transcriptionally active regions.

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“…With age, this balance is altered and the misfolded shape overwhelms the PQC system, halting protein synthesis and increasing chaperone production. Molecular chaperones are therefore considered promising candidates for the treatment of neurodegenerative diseases [ 277 , 278 ]. Recent studies have shown that natural compounds have neuroprotective effects and have therapeutic potential for AD.…”

Section: Ferroptosismentioning

confidence: 99%

Regulated cell death: discovery, features and implications for neurodegenerative diseases

Cui

Zhao

et al. 2021

Cell Commun Signal

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Regulated cell death (RCD) is a ubiquitous process in living organisms that is essential for tissue homeostasis or to restore biological balance under stress. Over the decades, various forms of RCD have been reported and are increasingly being found to involve in human pathologies and clinical outcomes. We focus on five high-profile forms of RCD, including apoptosis, pyroptosis, autophagy-dependent cell death, necroptosis and ferroptosis. Cumulative evidence supports that not only they have different features and various pathways, but also there are extensive cross-talks between modes of cell death. As the understanding of RCD pathway in evolution, development, physiology and disease continues to improve. Here we review an updated classification of RCD on the discovery and features of processes. The prominent focus will be placed on key mechanisms of RCD and its critical role in neurodegenerative disease. Graphical Abstract

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DAXX represents a new type of protein-folding enabler

Cited by 58 publications

References 39 publications

Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen

Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen

Interplay between PML NBs and HIRA for H3.3 dynamics following type I interferon stimulus

Regulated cell death: discovery, features and implications for neurodegenerative diseases

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