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Pumilio2 Promotes Growth of Mature Neurons.

ABSTRACT: RNA-binding proteins (RBPs) are essential regulators controlling both the cellular transcriptome and translatome. These processes enable cellular plasticity, an important prerequisite for growth. Cellular growth is a complex, tightly controlled process. Using cancer cells as model, we looked for RBPs displaying strong expression in published transcriptome datasets. Interestingly, we found the Pumilio (Pum) protein family to be highly expressed in all these cells. Moreover, we observed that Pum2 is regulated by basic fibroblast growth factor (bFGF). bFGF selectively enhances protein levels of Pum2 and the eukaryotic initiation factor 4E (eIF4E). Exploiting atomic force microscopy and in vitro pulldown assays, we show that Pum2 selects for eIF4E mRNA binding. Loss of Pum2 reduces eIF4E translation. Accordingly, depletion of Pum2 led to decreased soma size and dendritic branching of mature neurons, which was accompanied by a reduction in essential growth factors. In conclusion, we identify Pum2 as an important growth factor for mature neurons. Consequently, it is tempting to speculate that Pum2 may promote cancer growth.

SUBMITTER: Schieweck R

PROVIDER: S-EPMC8396670 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Pumilio2 Promotes Growth of Mature Neurons.

Schieweck Rico R Schöneweiss Elisa-Charlott EC Harner Max M Rieger Daniela D Illig Christin C Saccà Barbara B Popper Bastian B Kiebler Michael A MA

International journal of molecular sciences 20210820 16

RNA-binding proteins (RBPs) are essential regulators controlling both the cellular transcriptome and translatome. These processes enable cellular plasticity, an important prerequisite for growth. Cellular growth is a complex, tightly controlled process. Using cancer cells as model, we looked for RBPs displaying strong expression in published transcriptome datasets. Interestingly, we found the Pumilio (Pum) protein family to be highly expressed in all these cells. Moreover, we observed that Pum2 ...[more]

PMID: 34445704

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Project description:Alphaviruses are enveloped, positive-sense RNA viruses that are important causes of viral encephalomyelitis. Sindbis virus (SINV) infects the neurons of rodents and is a model for studying factors that regulate infection of neuronal cells. The outcome of alphavirus infection of the central nervous system is dependent on neuronal maturation status. Differentiated mature neurons survive and control viral replication better than undifferentiated immature neurons. The cellular factors involved in age-dependent susceptibility include higher levels of antiapoptotic and innate immune factors in mature neurons. Because NF-?B pathway activation is required for the initiation of both apoptosis and the host antiviral response, we analyzed the role of NF-?B during SINV infection of differentiated and undifferentiated rat neuronal cells. SINV infection induced canonical NF-?B activation, as evidenced by the degradation of I?B? and the phosphorylation and nuclear translocation of p65. Inhibition or deletion of the upstream I?B kinase substantially reduced SINV replication in differentiated but not in undifferentiated neuronal cells or mouse embryo fibroblasts. NF-?B inhibition did not affect the establishment of infection, replication complex formation, the synthesis of nonstructural proteins, or viral RNA synthesis in differentiated neurons. However, the translation of structural proteins was impaired, phosphorylation of the ? subunit of eukaryotic translation initiation factor 2 (eIF2?) was decreased, and host protein synthesis was maintained, suggesting that NF-?B activation was involved in the regulation of translation during infection of mature neurons. Inhibition or deletion of double-stranded RNA-activated protein kinase (PKR) also decreased eIF2? phosphorylation, the translation of viral structural proteins, and virus production. Therefore, canonical NF-?B activation synergizes with PKR to promote SINV replication in differentiated neurons by facilitating viral structural protein translation.IMPORTANCE Mosquito-borne alphaviruses are a significant and growing cause of viral encephalomyelitis worldwide. The outcome of alphaviral neuronal infections is host age dependent and greatly affected by neuronal maturation status, with differentiated, mature neurons being more resistant to infection than undifferentiated, immature neurons. The biological factors that change during neuronal maturation and that influence the outcome of viral infection are currently only partially defined. These studies investigated the role of NF-?B in determining the outcome of alphaviral infection in mature and immature neurons. Inhibition of canonical NF-?B activation decreased alphavirus replication in mature neurons by regulating protein synthesis and limiting the production of the viral structural proteins but had little effect on viral replication in immature neurons or fibroblasts. Therefore, NF-?B is a signaling pathway that influences the maturation-dependent outcome of alphaviral infection in neurons and that highlights the importance of cellular context in determining the effects of signal pathway activation.

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Pumilio2 Promotes Growth of Mature Neurons.

Publications

Pumilio2 Promotes Growth of Mature Neurons.

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