Translation of myelin basic protein mRNA in oligodendrocytes is regulated by integrin activation and hnRNP-K

Laursen, Lisbeth S.; Chan, Colin W.; ffrench‐Constant, Charles

doi:10.1083/jcb.201007014

Cited by 99 publications

(103 citation statements)

References 53 publications

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“…Similar to results with knockdown of tumor overexpressed gene, transport of MBP mRNA-containing granules appears unaffected in the absence of hnRNP F as hnRNP A2 and MBP distribution throughout the cytoplasm of oligodendrocytes appears normal. In contrast, the knockdown of hnRNP K leads to an accumulation of transport granules at oligodendroglial process branch points, although reduced hnRNP A2 levels result in a cytoplasmic retention of granules (26). Our work, where overexpression or reduction of hnRNP F shows similar effects in the luciferase assays, suggests that balanced levels of hnRNP F are required to form fully functional MBP mRNA transport granules, thus facilitating protein synthesis (Fig.…”

Section: Regulated Localization and Translation Of Mbp Mrna Insupporting

confidence: 45%

“…Given the fact that other myelin proteins are unaffected by hnRNP F manipulation, this regulation of MBP seems to be specific and not a general effect on myelin protein synthesis. Interestingly, the down-regulation of other MBP mRNA granule components such as tumor overexpressed gene, hnRNP A2, and hnRNP K also results in decreased MBP levels (26,50). Importantly, in our experiments hnRNP A2 expression levels remain unaltered, which emphasizes a direct effect of hnRNP F and excludes a secondary effect by hnRNP A2.…”

Section: Regulated Localization and Translation Of Mbp Mrna Inmentioning

confidence: 99%

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Heterogeneous Nuclear Ribonucleoprotein (hnRNP) F Is a Novel Component of Oligodendroglial RNA Transport Granules Contributing to Regulation of Myelin Basic Protein (MBP) Synthesis

White

Gonsior

Bauer

et al. 2012

Journal of Biological Chemistry

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Section: Regulated Localization and Translation Of Mbp Mrna Insupporting

confidence: 45%

Section: Regulated Localization and Translation Of Mbp Mrna Inmentioning

confidence: 99%

Heterogeneous Nuclear Ribonucleoprotein (hnRNP) F Is a Novel Component of Oligodendroglial RNA Transport Granules Contributing to Regulation of Myelin Basic Protein (MBP) Synthesis

White

Gonsior

Bauer

et al. 2012

Journal of Biological Chemistry

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“…This is compatible with the previous observation that hnRNP K binds to and thereby regulates translation of the mRNA of cytoskeleton genes and myelin basic protein. 32,33 Binding of hnRNP K to RNA is mediated by three KH domains within hnRNP K that act synergistically to provide both high-affinity binding and specificity (Figure 2). 24,25 Hence, loss of only a single KH domain dramatically reduces the RNA binding capacity of hnRNP K. 25 GrM cleaved hnRNP K at least at five independent sites, including Leu 125 , Leu 133 , and Met 359 , that are located in two apparent proteolysissensitive hot spots, thereby dissecting the functional KH domains (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication

et al. 2012

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Human cytomegalovirus (HCMV) is the most frequent viral cause of congenital defects and HCMV infection in immunocompromised patients may trigger devastating disease. Cytotoxic lymphocytes control HCMV by releasing granzymes towards virus-infected cells. In mice, granzyme M (GrM) has a physiological role in controlling murine CMV infection. However, the underlying mechanism remains poorly understood. In this study, we showed that human GrM was expressed by HCMV-specific CD8 þ T cells both in latently infected healthy individuals and in transplant patients during primary HCMV infection. We identified host cell heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a physiological GrM substrate. GrM most efficiently cleaved hnRNP K in the presence of RNA at multiple sites, thereby likely destroying hnRNP K function. Host cell hnRNP K was essential for HCMV replication not only by promoting viability of HCMV-infected cells but predominantly by regulating viral immediate-early 2 (IE2) protein levels. Furthermore, hnRNP K interacted with IE2 mRNA. Finally, GrM decreased IE2 protein expression in HCMV-infected cells. Our data suggest that targeting of hnRNP K by GrM contributes to the mechanism by which cytotoxic lymphocytes inhibit HCMV replication. This is the first evidence that cytotoxic lymphocytes target host cell proteins to control HCMV infections.

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“…The RTS includes the binding site for heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (Hoek et al, 1998;Munro et al, 1999), a protein that is known to be necessary for transport of the mRNA (Kwon et al, 1999;Laursen et al, 2011). More recent experiments have identified additional proteins associated with hnRNP-A2 or the RTS.…”

Section: Introductionmentioning

confidence: 99%

Transport and translation of MBP mRNA is differentially regulated by distinct hnRNP proteins

Torvund-Jensen

Steengaard

Reimer

et al. 2014

Journal of Cell Science

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In the developing nervous system, abundant synthesis of myelin basic protein (MBP) in oligodendrocytes is required for the formation of compact myelin sheaths around axons. The MBP mRNA is known to be transported into the processes of oligodendrocytes. However, knowledge of the regulatory mechanisms that ensure the tight temporal and spatial control of MBP translation within these processes is limited. Here, we have identified novel regions within the 39-UTR of the MBP mRNA that are responsible for the regulation of its translation, and we have demonstrated that each of the mRNA-binding proteins heterogeneous nuclear ribonucleoprotein (hnRNP)-A2, hnRNP-K and hnRNP-E1 serve distinct functions to regulate controlled and localized protein synthesis. hnRNP-A2 is responsible for mRNA transport, not for translational inhibition. By contrast, hnRNP-K and hnRNP-E1 play opposing roles in the translational regulation of MBP mRNA. We have identified shared binding sites within the 39-UTR, and show that translation is promoted by the exchange of inhibitory hnRNP-E1 for stimulatory hnRNP-K. We further show that this molecular switch in the MBP messenger RNA-ribonucleoprotein (mRNP) complex, which regulates the synthesis of MBP, is important for the normal growth and extension of myelin sheets.

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Translation of myelin basic protein mRNA in oligodendrocytes is regulated by integrin activation and hnRNP-K

Abstract: α6β1-integrin interacts with hnRNP-K, an mRNA-binding protein, during oligodendrocyte differentiation to promote translation of MBP mRNA and myelin synthesis.

Cited by 99 publications

References 53 publications

Heterogeneous Nuclear Ribonucleoprotein (hnRNP) F Is a Novel Component of Oligodendroglial RNA Transport Granules Contributing to Regulation of Myelin Basic Protein (MBP) Synthesis

Heterogeneous Nuclear Ribonucleoprotein (hnRNP) F Is a Novel Component of Oligodendroglial RNA Transport Granules Contributing to Regulation of Myelin Basic Protein (MBP) Synthesis

Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication

Transport and translation of MBP mRNA is differentially regulated by distinct hnRNP proteins

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