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Progress in 7SK ribonucleoprotein structural biology.

ABSTRACT: The 7SK ribonucleoprotein (RNP) is a dynamic and multifunctional regulator of RNA Polymerase II (RNAPII) transcription in metazoa. Comprised of the non-coding 7SK RNA, core proteins, and numerous accessory proteins, the most well-known 7SK RNP function is the sequestration and inactivation of the positive transcription elongation factor b (P-TEFb). More recently, 7SK RNP has been shown to regulate RNAPII transcription through P-TEFb-independent pathways. Due to its fundamental role in cellular function, dysregulation has been linked with human diseases including cancers, heart disease, developmental disorders, and viral infection. Significant advances in 7SK RNP structural biology have improved our understanding of 7SK RNP assembly and function. Here, we review progress in understanding the structural basis of 7SK RNA folding, biogenesis, and RNP assembly.

SUBMITTER: Camara MB

PROVIDER: S-EPMC10083321 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Progress in 7SK ribonucleoprotein structural biology.

Camara Momodou B MB Sobeh Amr M AM Eichhorn Catherine D CD

Frontiers in molecular biosciences 20230327

The 7SK ribonucleoprotein (RNP) is a dynamic and multifunctional regulator of RNA Polymerase II (RNAPII) transcription in metazoa. Comprised of the non-coding 7SK RNA, core proteins, and numerous accessory proteins, the most well-known 7SK RNP function is the sequestration and inactivation of the positive transcription elongation factor b (P-TEFb). More recently, 7SK RNP has been shown to regulate RNAPII transcription through P-TEFb-independent pathways. Due to its fundamental role in cellular f ...[more]

PMID: 37051324

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Project description: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. Author summary For intracellular replication, Coxiella burnetii depends on a functional type IV secretion system, which is utilized to inject ~150 virulence factors, so called effector proteins, into the host cell cytosol. Activities have only been established for few of them. These effector proteins interfere with vesicular trafficking, autophagy, lipid metabolism, apoptosis, and transcription by binding and manipulating the activity of host cell proteins. Here, we report that the C. burnetii T4SS effector protein AnkG (CBU0781, Q83DF6) binds to the host cell DExD box helicase 21 (DDX21) as well as to several host cell RNAs, including the small regulatory 7SK RNA, which is an important regulator of the positive elongation factor b (pTEFb). AnkG interferes with the function of the 7SK small nuclear ribonucleoprotein (7SK snRNP) complex, leading to significant changes in host cell transcription and ensuring host cell survival. AnkG activity is essential for efficient intracellular replication of C. burnetii and its ability to inhibit apoptosis. In summary, we identified a novel process by which a bacterial effector protein manipulates the host cell for its own benefit.

Dataset Information

Progress in 7SK ribonucleoprotein structural biology.

Publications

Progress in 7SK ribonucleoprotein structural biology.

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