Stabilize and connect: the role of LARP7 in nuclear non-coding RNA metabolism

Hasler, Daniele; Meister, Gunter; Fischer, Utz

doi:10.1080/15476286.2020.1767952

“…Pof8 shows the most similarity with LARP7 proteins. Members of this family have predominantly been studied in the context of the 7SK complex 22 . However, recently additional roles in the context of other RNPs have been described, including a function for LARP7 as a molecular bridge between U6 snRNA and a subset of box C/D small nucleolar RNAs that guide U6 2′-O-methylation 23 , 24 .…”

Section: Introductionmentioning

confidence: 99%

A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis

Páez-Moscoso

¹

,

Ho

²

,

Pan

³

et al. 2022

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Telomerase reverse transcriptase (TERT) and the noncoding telomerase RNA (TR) subunit constitute the core of telomerase. Additional subunits are required for ribonucleoprotein complex assembly and in some cases remain stably associated with the active holoenzyme. Pof8, a member of the LARP7 protein family is such a constitutive component of telomerase in fission yeast. Using affinity purification of Pof8, we have identified two previously uncharacterized proteins that form a complex with Pof8 and participate in telomerase biogenesis. Both proteins participate in ribonucleoprotein complex assembly and are required for wildtype telomerase activity and telomere length maintenance. One factor we named Thc1 (Telomerase Holoenzyme Component 1) shares structural similarity with the nuclear cap binding complex and the poly-adenosine ribonuclease (PARN), the other is the ortholog of the methyl phosphate capping enzyme (Bin3/MePCE) in metazoans and was named Bmc1 (Bin3/MePCE 1) to reflect its evolutionary roots. Thc1 and Bmc1 function together with Pof8 in recognizing correctly folded telomerase RNA and promoting the recruitment of the Lsm2-8 complex and the catalytic subunit to assemble functional telomerase.

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“…shows most similarity with LARP7 proteins. Members of this family have predominantly been studied in the context of the 7SK complex 22 . However, recently additional roles in the context of other RNPs have been described, including a function for LARP7 as a molecular bridge between U6 snRNA and a subset of box C/D small nucleolar RNAs that guide U6 2'-O-methylation 23,24 .…”

Section: Introductionmentioning

confidence: 99%

A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis

Páez-Moscoso

¹

,

Ho

²

,

Pan

³

et al. 2021

Preprint

2

3

0

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Telomerase reverse transcriptase (TERT) and the noncoding telomerase RNA (TR) subunit constitute the core of telomerase. Additional subunits are required for ribonucleoprotein complex assembly and in some cases remain stably associated with the active holoenzyme. Pof8, a member of the LARP7 protein family is such a constitutive component of telomerase in fission yeast. Using affinity purification of Pof8, we have identified two previously uncharacterized proteins that form a complex with Pof8 and participate in telomerase biogenesis. Both proteins participate in ribonucleoprotein complex assembly and are required for wildtype telomerase activity and telomere length maintenance. One factor we named Thc1 (Telomerase Holoenzyme Component 1) shares structural similarity with the nuclear cap binding complex and the poly-adenosine ribonuclease (PARN), the other is the ortholog of the methyl phosphate capping enzyme (Bin3/MePCE) in metazoans and was named Bmc1 (Bin3/MePCE 1) to reflect its evolutionary roots. Thc1 and Bmc1 function together with Pof8 in recognizing correctly folded telomerase RNA and promoting the recruitment of the Lsm2-8 complex and the catalytic subunit to assemble functional telomerase.

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“…To elicit whether the co-precipitation of AnkG to DDX21 depends on interaction of AnkG with the 7SK snRNP, we utilized ΔLARP7 HEK293T cells for co-immunoprecipitation experiments [ 27 ]. As LARP7 is an important scaffolding protein of the 7SK snRNP complex, its deletion triggers degradation of the complex [ 28 , 29 ]. HA-tagged DDX21 co-precipitated with GFP-NLS-AnkG and GFP-AnkG 1-28 , but not with GFP in control cells and in ΔLARP7 cells, demonstrating that the interaction of AnkG with DDX21 is independent of the 7SK snRNP complex ( Fig 5 ).…”

Section: Resultsmentioning

confidence: 99%

The Coxiella burnetii T4SS effector protein AnkG hijacks the 7SK small nuclear ribonucleoprotein complex for reprogramming host cell transcription

Cordsmeier

¹

,

Rinkel

²

,

Jeninga

³

et al. 2022

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Inhibition of host cell apoptosis is crucial for survival and replication of several intracellular bacterial pathogens. To interfere with apoptotic pathways, some pathogens use specialized secretion systems to inject bacterial effector proteins into the host cell cytosol. One of these pathogens is the obligate intracellular bacterium Coxiella burnetii, the etiological agent of the zoonotic disease Q fever. In this study, we analyzed the molecular activity of the anti-apoptotic T4SS effector protein AnkG (CBU0781) to understand how C. burnetii manipulates host cell viability. We demonstrate by co- and RNA-immunoprecipitation that AnkG binds to the host cell DExD box RNA helicase 21 (DDX21) as well as to the host cell 7SK small nuclear ribonucleoprotein (7SK snRNP) complex, an important regulator of the positive transcription elongation factor b (P-TEFb). The co-immunoprecipitation of AnkG with DDX21 is probably mediated by salt bridges and is independent of AnkG-7SK snRNP binding, and vice versa. It is known that DDX21 facilitates the release of P-TEFb from the 7SK snRNP complex. Consistent with the documented function of released P-TEFb in RNA Pol II pause release, RNA sequencing experiments confirmed AnkG-mediated transcriptional reprogramming and showed that expression of genes involved in apoptosis, trafficking, and transcription are influenced by AnkG. Importantly, DDX21 and P-TEFb are both essential for AnkG-mediated inhibition of host cell apoptosis, emphasizing the significance of the interaction of AnkG with both, the DDX21 protein and the 7SK RNA. In line with a critical function of AnkG in pathogenesis, the AnkG deletion C. burnetii strain was severely affected in its ability to inhibit host cell apoptosis and to generate a replicative C. burnetii-containing vacuole. In conclusion, the interference with the activity of regulatory host cell RNAs mediated by a bacterial effector protein represent a novel mechanism through which C. burnetii modulates host cell transcription, thereby enhancing permissiveness to bacterial infection.

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Stabilize and connect: the role of LARP7 in nuclear non-coding RNA metabolism

Cited by 16 publications

References 142 publications

A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis

A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis

A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis

The Coxiella burnetii T4SS effector protein AnkG hijacks the 7SK small nuclear ribonucleoprotein complex for reprogramming host cell transcription

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