Arsenic trioxide stimulates SUMO‐2/3 modification leading to RNF4‐dependent proteolytic targeting of PML

Weisshaar, Stefan R.; Keusekotten, Kirstin; Krause, Anke; Horst, Christiane; Springer, Helen M.; Göttsche, Kerstin; Dohmen, R. Jürgen; Praefcke, Gerrit J. K.

doi:10.1016/j.febslet.2008.08.008

Cited by 93 publications

(91 citation statements)

References 21 publications

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“…As SUMO chains are associated exclusively with SUMO2/3 conjugation, this observation indicates that NS1 is likely preferentially SUMOylated by SUMO2/3. SUMO2/3 chains are known to stimulate the polyubiquitination of some SUMOylated proteins, therefore triggering their proteasomal degradation (71)(72)(73)(74). However, our data indicate that SUMOylation does not affect the stability of NS1 (see below).…”

Section: Discussioncontrasting

confidence: 54%

“…Importantly, for certain substrates, SUMOylation with SUMO2/3 is known to trigger the formation of long poly-SUMO chains that are recognized by ubiquitin ligases and lead to the polyubiquitinylation of the SUMOylated substrate, which in turns leads to their proteasomal degradation (71)(72)(73)(74). Data obtained during the execution of these studies revealed the formation of polySUMOylated NS1 in the presence of wt-ASL and mut-ASL (see, for example, Fig.…”

Section: Ns1 Sumoylation Affects Viral Growth In Ifn-competent and Ifmentioning

confidence: 98%

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SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

Santos

Pal

Chacon

et al. 2013

J Virol

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Our pioneering studies on the interplay between the small ubiquitin-like modifier (SUMO) and influenza A virus identified the nonstructural protein NS1 as the first known SUMO target of influenza virus and one of the most abundantly SUMOylated influenza virus proteins. Here, we further characterize the role of SUMOylation for the A/Puerto Rico/8/1934 (PR8) NS1 protein, demonstrating that NS1 is SUMOylated not only by SUMO1 but also by SUMO2/3 and mapping the main SUMOylation sites in NS1 to residues K219 and K70. Furthermore, by using SUMOylatable and non-SUMOylatable forms of NS1 and an NS1-specific artificial SUMO ligase (ASL) that increases NS1 SUMOylation ϳ4-fold, we demonstrate that SUMOylation does not affect the stability or cellular localization of PR8 NS1. However, NS1's ability to be SUMOylated appears to affect virus multiplication, as indicated by the delayed growth of a virus expressing the non-SUMOylatable form of NS1 in the interferon (IFN)-competent MDCK cell line. Remarkably, while a non-SUMOylatable form of NS1 exhibited a substantially diminished ability to neutralize IFN production, increasing NS1 SUMOylation beyond its normal levels also exerted a negative effect on its IFN-blocking function. This observation indicates the existence of an optimal level of NS1 SUMOylation that allows NS1 to achieve maximal activity and suggests that the limited amount of SUMOylation normally observed for most SUMO targets may correspond to an optimal level that maximizes the contribution of SUMOylation to protein function. Finally, protein cross-linking data suggest that SUMOylation may affect NS1 function by regulating the abundance of NS1 dimers and trimers in the cell.

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Section: Discussioncontrasting

confidence: 54%

Section: Ns1 Sumoylation Affects Viral Growth In Ifn-competent and Ifmentioning

confidence: 98%

SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

Santos

Pal

Chacon

et al. 2013

J Virol

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“…Although different types of stress trigger increases in global SUMO conjugation levels, arsenic very specifically triggers sumoylation of PML (or the PML-RARα fusion). Recent work confirmed that the modified PML then becomes an in vivo target of the STUbL RNF4 [96][97][98][99]. Specifically, ATO-induced PML sumoylation correlates with its subsequent K48-linked polyubiquitination and degradation by the proteasome [100].…”

Section: Pml: Protein Degraded By Sumo-dependent Ubiquitination Pathwaymentioning

confidence: 78%

Nuclear organization in genome stability: SUMO connections

2011

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Recent findings show that chromatin dynamics and nuclear organization are not only important for gene regulation and DNA replication, but also for the maintenance of genome stability. In yeast, nuclear pores play a role in the maintenance of genome stability by means of the evolutionarily conserved family of SUMO-targeted Ubiquitin ligases (STUbLs). The yeast Slx5/Slx8 STUbL associates with a class of DNA breaks that are shifted to nuclear pores. Functionally Slx5/Slx8 are needed for telomere maintenance by an unusual recombination-mediated pathway. The mammalian STUbL RNF4 associates with Promyelocytic leukaemia (PML) nuclear bodies and regulates PML/PMLfusion protein stability in response to arsenic-induced stress. A subclass of PML bodies support telomere maintenance by the ALT pathway in telomerase-deficient tumors. Perturbation of nuclear organization through either loss of pore subunits in yeast, or PML body perturbation in man, can lead to gene amplifications, deletions, translocations or endto-end telomere fusion events, thus implicating SUMO and STUbLs in the subnuclear organization of select repair events.

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“…In addition, SUMO-targeted ubiquitin ligases recognize SUMOylated proteins and polyubiquitylate them, targeting them for degradation (Prudden et al, 2007;Sun et al, 2007;Xie et al, 2007;Mullen and Brill, 2008;Weisshaar et al, 2008). Interestingly, PML is the only protein in mammalian cells identified so far that is targeted by the RNF4 SUMOtargeted ubiquitin ligases (Lallemand-Breitenbach et al, 2008;Tatham et al, 2008), and E1A had an observable effect on PML localization that was specifically dependent on binding UBC9 (Figure 6).…”

Section: E1a Interaction With Ubc9mentioning

confidence: 99%

Identification of a molecular recognition feature in the E1A oncoprotein that binds the SUMO conjugase UBC9 and likely interferes with polySUMOylation

et al. 2010

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Hub proteins have central roles in regulating cellular processes. By targeting a single cellular hub, a viral oncogene may gain control over an entire module in the cellular interaction network that is potentially comprised of hundreds of proteins. The adenovirus E1A oncoprotein is a viral hub that interacts with many cellular hub proteins by short linear motifs/molecular recognition features (MoRFs). These interactions transform the architecture of the cellular protein interaction network and virtually reprogram the cell. To identify additional MoRFs within E1A, we screened portions of E1A for their ability to activate yeast pseudohyphal growth or differentiation. This identified a novel functional region within E1A conserved region 2 comprised of the sequence EVIDLT. This MoRF is necessary and sufficient to bind the N-terminal region of the SUMO conjugase UBC9, which also interacts with SUMO noncovalently and is involved in polySUMOylation. Our results suggest that E1A interferes with polySUMOylation, but not with monoSUMOylation. These data provide the first insight into the consequences of the interaction of E1A with UBC9, which was initially described in 1996. We further demonstrate that polySUMOylation regulates pseudohyphal growth and promyelocytic leukemia body reorganization by E1A. In conclusion, the interaction of the E1A oncogene with UBC9 mimics the normal binding between SUMO and UBC9 and represents a novel mechanism to modulate polySUMOylation.

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Arsenic trioxide stimulates SUMO‐2/3 modification leading to RNF4‐dependent proteolytic targeting of PML

Cited by 93 publications

References 21 publications

SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

Nuclear organization in genome stability: SUMO connections

Identification of a molecular recognition feature in the E1A oncoprotein that binds the SUMO conjugase UBC9 and likely interferes with polySUMOylation

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