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Dimerization of p15RS mediated by a leucine zipper-like motif is critical for its inhibitory role on Wnt signaling.

ABSTRACT: We previously demonstrated that p15RS, a newly discovered tumor suppressor, inhibits Wnt/?-catenin signaling by interrupting the formation of ?-catenin·TCF4 complex. However, it remains unclear how p15RS helps exert such an inhibitory effect on Wnt signaling based on its molecular structure. In this study, we reported that dimerization of p15RS is required for its inhibition on the transcription regulation of Wnt-targeted genes. We found that p15RS forms a dimer through a highly conserved leucine zipper-like motif in the coiled-coil terminus domain. In particular, residues Leu-248 and Leu-255 were identified as being responsible for p15RS dimerization, as mutation of these two leucines into prolines disrupted the homodimer formation of p15RS and weakened its suppression of Wnt signaling. Functional studies further confirmed that mutations of p15RS at these residues results in diminishment of its inhibition on cell proliferation and tumor formation. We therefore concluded that dimerization of p15RS governed by the leucine zipper-like motif is critical for its inhibition of Wnt/?-catenin signaling and tumorigenesis.

SUBMITTER: Fan X

PROVIDER: S-EPMC5961044 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Dimerization of p15RS mediated by a leucine zipper-like motif is critical for its inhibitory role on Wnt signaling.

Fan Xuanzi X Zhao Juan J Ren Fangli F Wang Yinyin Y Feng Yarui Y Ding Lidan L Zhao Linpeng L Shang Yu Y Li Jun J Ni Jianquan J Jia Baoqing B Liu Yule Y Chang Zhijie Z

The Journal of biological chemistry 20180404 20

We previously demonstrated that p15RS, a newly discovered tumor suppressor, inhibits Wnt/β-catenin signaling by interrupting the formation of β-catenin·TCF4 complex. However, it remains unclear how p15RS helps exert such an inhibitory effect on Wnt signaling based on its molecular structure. In this study, we reported that dimerization of p15RS is required for its inhibition on the transcription regulation of Wnt-targeted genes. We found that p15RS forms a dimer through a highly conserved leucin ...[more]

PMID: 29618509

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Project description:Productive viral infection often depends on the manipulation of the cytoskeleton. Herpesviruses, including rhesus monkey rhadinovirus (RRV) and its close homolog, the oncogenic human gammaherpesvirus Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV8), exploit microtubule (MT)-based retrograde transport to deliver their genomes to the nucleus. Subsequently, during the lytic phase of the life cycle, the maturing viral particles undergo orchestrated translocation to specialized regions within the cytoplasm, leading to tegumentation, secondary envelopment, and then egress. As a result, we hypothesized that RRV might induce changes in the cytoskeleton at both early and late stages of infection. Using confocal imaging, we found that RRV infection led to the thickening and acetylation of MTs emanating from the MT-organizing center (MTOC) shortly after viral entry and more pronounced and diffuse MT reorganization during peak stages of lytic gene expression and virion production. We subsequently identified open reading frame 52 (ORF52), a multifunctional and abundant tegument protein, as being the only virally encoded component responsible for these cytoskeletal changes. Mutational and modeling analyses indicated that an evolutionarily conserved, truncated leucine zipper motif near the N terminus as well as a strictly conserved arginine residue toward the C terminus of ORF52 play critical roles in its ability to rearrange the architecture of the MT cytoskeleton. Taken together, our findings combined with data from previous studies describing diverse roles for ORF52 suggest that it likely binds to different cellular components, thereby allowing context-dependent modulation of function.IMPORTANCE A thorough understanding of the processes governing viral infection includes knowledge of how viruses manipulate their intracellular milieu, including the cytoskeleton. Altering the dynamics of actin or MT polymerization, for example, is a common strategy employed by viruses to ensure efficient entry, maturation, and egress as well as the avoidance of antiviral defenses through the sequestration of key cellular factors. We found that infection with RRV, a homolog of the human pathogen KSHV, led to perinuclear wrapping by acetylated MT bundles and identified ORF52 as the viral protein underlying these changes. Remarkably, incoming virions were able to supply sufficient ORF52 to induce MT thickening and acetylation near the MTOC, potentially aiding in the delivery viral genomes to the nucleus. Although the function of MT alterations during late stages of infection requires further study, ORF52 shares functional and structural similarities with alphaherpesvirus VP22, underscoring the evolutionary importance of MT cytoskeletal manipulations for this virus family.

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Dimerization of p15RS mediated by a leucine zipper-like motif is critical for its inhibitory role on Wnt signaling.

Publications

Dimerization of p15RS mediated by a leucine zipper-like motif is critical for its inhibitory role on Wnt signaling.

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