Identification of two independent SUMO-interacting motifs in Daxx: Evolutionary conservation from Drosophila to humans and their biochemical functions

Santiago, Aleixo; Godsey, Adam; Hossain, Jamil; Zhao, Lisa; Liao, Daiqing

doi:10.4161/cc.8.1.7493

Cited by 32 publications

(65 citation statements)

References 54 publications

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“…If the result of silencing is prolonged viral survival due to latency or immune evasion, transcriptional silencing may well be a proviral strategy. In addition, the observation that in some cells cytoplasmic retention of pp71 is responsible for latency indicates that cellular homeostasis could play a major role in the efficiency of Daxx-mediated antiviral effects and influence the fate of the viral genome (96).…”

Section: Daxx Impairment By Virion Proteins: How Could It Work?mentioning

confidence: 99%

“…It is not clear what mechanisms retain a species barrier and prevent human pathogens from replicating in nonhuman cells or vice versa. Daxx possesses interspecies-conserved domains as well as species-specific variations, including differences between murine and human Daxx (96). For murine cytomegalovirus (MCMV), whose replication is restricted to murine cells, coexpression of a subset of HCMV tegument proteins, including pp71, could overcome the replication block in human cells (119).…”

Section: Daxx Impairment By Virion Proteins: Overcoming the Species Bmentioning

confidence: 99%

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Virion Factors That Target Daxx To Overcome Intrinsic Immunity

Schreiner

Wodrich

2013

J Virol

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bPML nuclear bodies and their associated functions are part of an intrinsic cellular mechanism aimed at maintaining transcriptional control over viral gene expression and preventing replication of invading viruses. To overcome these barriers, many viruses express early nonstructural, multifunctional proteins to support the viral replication cycle or modulate host immune responses. Virion proteins constituting the invading particle are traditionally investigated for their role in transport during entry or egress and in the assembly of new virions. The additional functions of virion proteins have largely been ignored, in contrast to those of their nonstructural counterparts. A number of recent reports suggest that several virion proteins may also play vital roles in gene activation processes, in particular by counteracting intrinsic immune mechanisms mediated by the PML nuclear body-associated cellular factors Daxx, ATRX, and Sp100. These virion proteins share several features with their more potent nonstructural counterparts, and they may serve to bridge the gap in the early phase of an infection until immediate early viral gene expression is established. In this review, we discuss how virion proteins are an integral part of gene regulation among several viral families and to what extent structural proteins of incoming virions may contribute to species barrier, latency, and oncogenesis.W hen viral genetic information is transferred from cell to cell, it must be compacted and transcriptionally inactivated for storage in the viral capsid during transport. This process needs to be actively reversed upon infection against cellular transcriptional repression through intrinsic antiviral mechanisms. An important factor in the cellular control of viral gene expression is death domain-associated protein (Daxx). Daxx was initially described as a modulator of apoptotic signaling (1), but recent reports suggest that Daxx plays an active role in gene regulation by repressing or modulating transcription through chromatin remodeling (2, 3). Daxx mainly cooperates with alpha-thalassemia retardation syndrome x-linked (ATRX), a putative member of the SNF2 family of ATP-dependent chromatin-remodeling proteins. In this repressive complex, ATRX acts as the core ATPase subunit, while Daxx is the targeting factor, leading to histone deacetylase (HDAC) recruitment (4-6).Daxx is found associated with the promyelocytic leukemia protein nuclear body (PML-NB) or chromatin. Association with PML-NB alleviates gene repression and activates apoptosis, while chromatin-bound Daxx represses transcription (7-9). It has been long established that PML-NBs are nuclear structures with antiviral activity, accumulating an expanding number of transient or constitutive cellular factors involved in transcriptional control, chromatin remodeling, genome integrity, apoptosis, and tumor suppression (10). Moreover, several PML-NB constituents can be induced by type I and II interferon (IFN), resulting in increased antiviral activity by attenuating viral gene exp...

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Section: Daxx Impairment By Virion Proteins: How Could It Work?mentioning

confidence: 99%

Section: Daxx Impairment By Virion Proteins: Overcoming the Species Bmentioning

confidence: 99%

Virion Factors That Target Daxx To Overcome Intrinsic Immunity

Schreiner

Wodrich

2013

J Virol

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“…Daxx is a well-known apoptosis regulator that acts primarily as a transcriptional regulator, although its status as a pro-or anti-apoptotic factor is debated (Michaelson, 2000;Salomoni and Khelifi, 2006;Shih et al, 2007). Daxx contains two well-characterized SUMO-interacting motifs (SIM) at its termini that allow it to interact with SUMOylated proteins in cells (Santiago et al, 2009;Chang et al, 2011;Escobar-Cabrera et al, 2011). In response to UV irradiation, Daxx appears to act as a pro-apoptotic protein downstream of PIAS1.…”

Section: Discussionmentioning

confidence: 99%

The SUMO ligase PIAS1 regulates UV-induced apoptosis by recruiting Daxx to SUMOylated foci

Sudharsan

Azuma

2012

Journal of Cell Science

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SummaryThe small ubiquitin-like modifier (SUMO) ligase PIAS1 (Protein Inhibitor of Activated Stat-1) has been shown to play a role in cellular stress response by SUMOylating several proteins that are involved in DNA repair, apoptosis and transcription. In this paper, we show that PIAS1 regulates ultraviolet (UV)-induced apoptosis by recruiting Death-associated protein 6 (Daxx) to PIAS1-generated SUMOfoci. Cells that ectopically express PIAS1, but not other PIASes, show increased sensitivity to UV irradiation, suggesting that PIAS1 has a distinct function in UV-dependent apoptosis. Domain analysis of PIAS1 indicates that both PIAS1 SUMO-ligase activity and the specific localization of PIAS1 through its N-terminal and C-terminal domains are essential for UV-induced cell death. Daxx colocalizes with PIAS1-generated SUMOylated foci, and the reduction of Daxx using RNAi alleviates UV-induced apoptosis in PIAS1-expressing cells. PIAS1-mediated recruitment of Daxx and apoptosis following UV irradiation are dependent upon the Daxx C-terminal SUMOinteracting motif (SIM). Overall, our data suggest that the pro-apoptotic protein Daxx specifically interacts with one or more substrates SUMOylated by PIAS1 and this interaction leads to apoptosis following UV irradiation.Key words: PIAS1, SUMO, Apoptosis, UV irradiation, Daxx IntroductionThe small ubiquitin-like modifier (SUMO) proteins regulate the activity, localization and/or stability of various cellular proteins through a reversible covalent modification or noncovalent interactions with their substrates (Geiss-Friedlander and Melchior, 2007). Three well-characterized SUMO isoforms, numbered 1 to 3, exist in vertebrates, and the gene for a fourth potential SUMO isoform (SUMO-4) has been identified; however, it is unclear whether SUMO-4 is expressed in all cells and whether it can be conjugated to other proteins. SUMO-1, SUMO-2 and SUMO-3 covalently attach to a substrate by forming an isopeptide linkage with one or more specific lysine residues on the protein. In addition, SUMO-2 and SUMO-3, which share 95% sequence identity, are known to form poly-SUMO chains (Johnson, 2004). SUMO modification involves the sequential transfer of a processed active SUMO protein from an E1 SUMO-activating enzyme to an E2 SUMO-conjugating enzyme and the subsequent covalent conjugation to the substrate in a reaction that involves a SUMO-E3 ligase. In their substrate-conjugated form, SUMO proteins can interact with other proteins containing a SUMO-interacting motif (SIM), which is characterized by YYXY or YXYY residues (where Y is a hydrophobic amino acid) and is often flanked by negatively charged residues (Song et al., 2004;Wilkinson and Henley, 2010). Therefore, protein modification by SUMO can lead to new protein-protein interaction modules.Since the first SUMO-conjugated protein was identified, the repertoire of SUMO-modified substrates has steadily increased. The diversity of SUMO substrates is presumably governed by a small number of SUMO E3 ligases that exist in cells. The PIAS (Protein...

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“…Based on its association with nuclear PML bodies, CAPN5 should also be SUMOylated and/or contain a SIM (32). SIM features include an acidic domain adjacent to a string of three of Val, Ile, and/or Leu amino acids (55)(56)(57). A putative SIM (KPEDEVLICI, aa 396 -405) in CAPN5 is contained within NLS2.…”

Section: Discussionmentioning

confidence: 99%

“…Mutating Ile 403 within NLS2 to Ala aborts the nuclear localization, indicating that the SIM motif plays a critical role in both the nuclear import and PML localization of CAPN5. Other PML partner proteins that contain SIMs include Daxx and SP100 in addition to PML itself (57,58).…”

Section: Discussionmentioning

confidence: 99%