Destabilization of YopE by the Ubiquitin-Proteasome Pathway Fine-Tunes Yop Delivery into Host Cells and Facilitates Systemic Spread ofYersinia enterocoliticain Host Lymphoid Tissue

ABSTRACTPathogenicYersiniaspecies inject a panel of Yop virulence proteins by type III protein secretion into host cells to modulate cellular defense responses. This enables the survival and dissemination of the bacteria in the host lymphoid tissue. We have previously shown that YopE of theY. enterocoliticaserogroup O8 is degraded in the host cell through the ubiquitin-proteasome pathway. YopE normally manipulates rearrangements of the actin cytoskeleton and triggers phagocytosis resistance. To shed light into the physiological role of YopE inactivation, we mutagenized the lysine polyubiquitin acceptor sites of YopE in theY. enterocoliticaserogroup O8 virulence plasmid. The resulting mutant strain escaped polyubiquitination and degradation of YopE and displayed increased intracellular YopE levels, which was accompanied by a pronounced cytotoxic effect on infected cells. Despite its intensified activity on cultured cells, theYersiniamutant with stabilized YopE showed reduced dissemination into liver and spleen following enteral infection of mice. Furthermore, the accumulation of degradation-resistant YopE was accompanied by the diminished delivery of YopP and YopH into cultured,Yersinia-infected cells. A role of YopE in the regulation of Yop translocation has already been described. Our results imply that the inactivation of YopE by the proteasome could be a tool to ensure intermediate intracellular YopE levels, which may effectuate optimized Yop injection into host cells. In this regard,Y. enterocoliticaO8 appears to exploit the host ubiquitin proteasome system to destabilize YopE and to fine-tune the activities of the Yop virulence arsenal on the infected host organism.

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Regulation of Bovine Papillomavirus Replicative Helicase E1 by the Ubiquitin-Proteasome Pathway

Journal of Virology ◽

10.1128/jvi.76.22.11350-11358.2002 ◽

2002 ◽

Vol 76 (22) ◽

pp. 11350-11358 ◽

Cited By ~ 17

Author(s):

Marie-Helene Malcles ◽

Nathalie Cueille ◽

Francisca Mechali ◽

Olivier Coux ◽

Catherine Bonne-Andrea

Keyword(s):

Cyclin E ◽

Degradation Pathway ◽

Host Cells ◽

Bovine Papillomavirus ◽

Free System ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Infected Cells ◽

Proteasome Pathway ◽

Replication Activity

ABSTRACT Papillomaviruses maintain their genomes in a relatively constant copy number as stable extrachromosomal plasmids in the nuclei of dividing host cells. The viral initiator of replication, E1, is not detected in papillomavirus-infected cells. Here, we present evidence that E1 encoded by bovine papillomavirus type 1 is an unstable protein that is degraded through the ubiquitin-proteasome pathway. In a cell-free system derived from Xenopus egg extracts, E1 degradation is regulated by both cyclin E/Cdk2 binding and E1 replication activity. Free E1 is readily ubiquitinated and degraded by the proteasome, while it becomes resistant to this degradation pathway when bound to cyclin E/Cdk2 complexes before the start of DNA synthesis. This stabilization is reversed in a process involving E1-dependent replication activity. In transiently transfected cells, E1 is also polyubiquitinated and accumulates when proteasome activity is inhibited. Thus, the establishment and maintenance of a stable number of papillomavirus genomes in latently infected cells are in part a function of regulated ubiquitin-mediated degradation of E1.

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Abstract 44: TAK1 Regulates Caspase 8 Activation and Necroptotic Signaling via Multiple Cell Death Checkpoints

Circulation Research ◽

10.1161/res.119.suppl_1.44 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Xaioyun Guo ◽

Haifeng Yin ◽

Yi Chen ◽

Lei Li ◽

Jing Li ◽

...

Keyword(s):

Cell Death ◽

Adaptor Protein ◽

Regulatory Mechanisms ◽

Caspase 8 ◽

Ubiquitin Proteasome Pathway ◽

Pathological Conditions ◽

Ubiquitin Proteasome ◽

Multiple Cell ◽

Proteasome Pathway

Necroptosis has emerged as a new form of programmed cell death implicated in a number of pathological conditions such as ischemic injury, neurodegenerative disease, and viral infection. Recent studies indicate that TGFβ-activated kinase 1 (TAK1) is nodal regulator of necroptotic cell death, but the underlying molecular regulatory mechanisms remain elusive. Here we reported that TAK1 regulates necroptotic signaling as well as caspase 8 activation through both NFκB-dependent and -independent mechanisms. Inhibition of TAK1 promoted TNFα-induced necroptosis through the induction of RIP1 phosphorylation/activation and necrosome formation, in the presence of ongoing caspase activation. Further, inhibition of TAK1 triggered two caspase 8 activation pathways through the induction of RIP1-FADD-caspase 8 complex as well as FLIP cleavage/degradation. Mechanistically, our data uncovered an essential role of the adaptor protein TRADD in caspase 8 activation and necrosome formation triggered by TAK1 inhibition. Moreover, ablation of the deubiqutinase CYLD prevented both apoptotic and necroptotic signaling induced by TAK1 inhibition, whereas deletion of the E3 ubiquitin ligase TRAF2 had the opposite effect. Finally, blocking the ubiquitin-proteasome pathway prevented the degradation of key necroptotic signaling proteins and necrosome formation. Thus we identified novel regulatory mechanisms underling the critical role of TAK1 in necroptotic signaling through regulation of multiple cell death checkpoints. Targeting key components of the necroptotic pathway (e.g., TRADD and CYLD) and the ubiquitin-proteasome pathway may represent novel therapeutic strategies for pathological conditions driven by necroptosis.

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The Role of the Ubiquitin–Proteasome Pathway in the Regulation of the Cellular Hypoxia Response

Protein Degradation Series ◽

10.1002/9783527619320.ch6b ◽

2008 ◽

pp. 132-148

Author(s):

Koh Nakayama ◽

Ze'ev Ronai

Keyword(s):

Hypoxia Response ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Cellular Hypoxia ◽

Proteasome Pathway

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Participation of the ubiquitin-proteasome pathway in rat oocyte activation

Zygote ◽

10.1017/s0967199405003114 ◽

2005 ◽

Vol 13 (1) ◽

pp. 87-95 ◽

Cited By ~ 2

Author(s):

Xin Tan ◽

An Peng ◽

Yong-Chao Wang ◽

Yue Wang ◽

Qing-Yuan Sun

Keyword(s):

Meiotic Division ◽

Polar Body ◽

Meiotic Spindle ◽

Oocyte Activation ◽

Parthenogenetic Activation ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Second Polar Body

The role of the ubiquitin-proteasome pathway (UPP) in mitosis is well known. However, its role in meiotic division is still poorly documented, especially in the activation of mammalian oocytes. In this study, the role of proteasome in the spontaneous and parthenogenetic activation of rat oocytes was investigated. We found that ALLN, an inhibitor of proteasome, when applied to metaphase II oocytes, inhibited spontaneous activation, blocked extrusion of the second polar body (PB) and caused the withdrawal of the partially extruded second PB. ALLN also inhibited the parthenogenetic activation induced by cycloheximide, but had no effect on the formation of pronuclei in activated eggs. In metaphase and anaphase, ubiquitin and proteasome localized to the meiotic spindle, concentrating on both sides of the oocyte–second PB boundary during PB extrusion. This pattern of cellular distribution suggests that UPP may have a role in regulating nuclear division and cytokinesis. Ubiquitin was seen to form a ring around the pronucleus, whereas proteasome was evenly distributed in the pronuclear region. Taken together, our results indicate that (1) UPP is required for the transitions of oocytes from metaphase II to anaphase II and from anaphase II to the end of meiosis; and (2) the UPP plays a role in cytokinesis of the second meiotic division.

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