The Bacterial Mucosal Immunotherapy MV130 Protects Against SARS-CoV-2 Infection and Improves COVID-19 Vaccines Immunogenicity

Carlos del Fresno, Juan García-Arriaza, Sarai Martínez-Cano, Ignacio Heras-Murillo, Aitor Jarit-Cabanillas, Joaquín Amores-Iniesta, Paola Brandi, Gillian Dunphy, Carmen Suay-Corredera, Maria Rosaria Pricolo, Natalia Vicente, Andrés López-Perrote, Sofía Cabezudo, Ana González-Corpas, Oscar Llorca, Jorge Alegre-Cebollada, Urtzi Garaigorta, Pablo Gastaminza, Mariano Esteban, and David Sancho.

Abstract: COVID-19-specific vaccines are efficient prophylactic weapons against SARS-CoV-2 virus. However, boosting innate responses may represent an innovative way to immediately fight future emerging viral infections or boost vaccines. MV130 is a mucosal immunotherapy, based on a mixture of whole heat-inactivated bacteria, that has shown clinical efficacy against recurrent viral respiratory infections. Herein, we show that the prophylactic intranasal administration of this immunotherapy confers heterologous protection against SARS-CoV-2 infection in susceptible K18-hACE2 mice. Furthermore, in C57BL/6 mice, prophylactic administration of MV130 improves the immunogenicity of two different COVID-19 vaccine formulations targeting the SARS-CoV-2 spike (S) protein, inoculated either intramuscularly or intranasally. Independently of the vaccine candidate and vaccination route used, intranasal prophylaxis with MV130 boosted S-specific responses, including CD8+-T cell activation and the production of S-specific mucosal IgA antibodies. Therefore, the bacterial mucosal immunotherapy MV130 protects against SARS-CoV-2 infection and improves COVID-19 vaccines immunogenicity.

LINK a la publicación.

CDK1 and PLK1 cooperate to regulate BICD2, dynein activation and recruitment to the nucleus as well as centrosome separation in G2/M

Núria Gallisà-Suñé, Paula Sànchez-Fernàndez-de-Landa, Fabian Zimmermann, Marina Serna, Joel Paz, Laura Regué, Oscar Llorca, Jens Lüders and Joan Roig

Abstract: The activity of dynein is regulated by a number of adaptors that mediate its interaction with dynactin, effectively activating the motor complex while also connecting it to different cargos. The regulation of adaptors is consequently central to dynein physiology, but remains largely unexplored. We now describe that one of the bestknown dynein adaptors, BICD2, is effectively activated through phosphorylation. In G2 phosphorylation of BICD2 by CDK1 promotes its interaction with PLK1. In turn, PLK1 phosphorylation of a single residue in the N-terminus of BICD2 results in a conformational change that facilitates interaction with dynein and dynactin, allowing the formation of active motor complexes. BICD2 phosphorylation is central for dynein recruitment to the nuclear envelope, centrosome tethering to the nucleus and centrosome separation in G2/M. This work reveals adaptor activation through phosphorylation as crucial for the spatiotemporal regulation of dynein activity.

LINK a la publicación.

Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma

Juan P Unfried, Mikel Marín-BaqueroÁngel Rivera-CalzadaNerea RazquinEva M Martín-CuevasSara de BragançaClara Aicart-RamosChristopher McCoyLaura Prats-MariRaquel Arribas-BosacomaLinda LeeStefano CarusoJessica Zucman-RossiBruno SangroGareth WilliamsFernando Moreno-HerreroOscar LlorcaSusan P Lees-MillerPuri Fortes

Abstract: Long noncoding RNAs (lncRNA) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis. NIHCOLE deficiency led to accumulation of DNA damage due to a specific decrease in the activity of the nonhomologous end-joining (NHEJ) pathway of DSB repair. DNA damage induction in NIHCOLE-depleted cells further decreased HCC cell growth. NIHCOLE was associated with DSB markers and recruited several molecules of the Ku70/Ku80 heterodimer. Further, NIHCOLE putative structural domains supported stable multimeric complexes formed by several NHEJ factors including Ku70/80, APLF, XRCC4, and DNA ligase IV. NHEJ reconstitution assays showed that NIHCOLE promoted the ligation efficiency of blunt-ended DSBs. Collectively, these data show that NIHCOLE serves as a scaffold and facilitator of NHEJ machinery and confers an advantage to HCC cells, which could be exploited as a targetable vulnerability. SIGNIFICANCE: This study characterizes the role of lncRNA NIHCOLE in DNA repair and cellular fitness in HCC, thus implicating it as a therapeutic target.See related commentary by Barcena-Varela and Lujambio, p. 4899.

LINK a la publicación.

Post-Translational Modification and Subcellular Compartmentalization: Emerging Concepts on the Regulation and Physiopathological Relevance of RhoGTPases

Inmaculada Navarro-Lérida,  Miguel SánchezÁlvarez and Miguel Ángel Del Pozo

Abstract: Cells and tissues are continuously exposed to both chemical and physical stimuli and dynamically adapt and respond to this variety of external cues to ensure cellular homeostasis, regulated development and tissue-specific differentiation. Alterations of these pathways promote disease progression—a prominent example being cancer. Rho GTPases are key regulators of the remodeling of cytoskeleton and cell membranes and their coordination and integration with different biological processes, including cell polarization and motility, as well as other signaling networks such as growth signaling and proliferation. Apart from the control of GTP–GDP cycling, Rho GTPase activity is spatially and temporally regulated by post-translation modifications (PTMs) and their assembly onto specific protein complexes, which determine their controlled activity at distinct cellular compartments. Although Rho GTPases were traditionally conceived as targeted from the cytosol to the plasma membrane to exert their activity, recent research demonstrates that active pools of different Rho GTPases also localize to endomembranes and the nucleus. In this review, we discuss how PTM-driven modulation of Rho GTPases provides a versatile mechanism for their compartmentalization and functional regulation. Understanding how the subcellular sorting of active small GTPase pools occurs and what its functional significance is could reveal novel therapeutic opportunities.

LINK a la publicación.

Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone

Mohinder PalHugo Muñoz-HernandezDennis BjorklundLihong ZhouGianluca DegliespostiJ Mark SkehelEmma L HeskethRebecca F ThompsonLaurence H PearlOscar Llorca and  Chrisostomos Prodromou

Abstract: The R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) complex, in collaboration with heat shock protein 90 (HSP90), functions as a chaperone for the assembly and stability of protein complexes, including RNA polymerases, small nuclear ribonucleoprotein particles (snRNPs), and phosphatidylinositol 3-kinase (PI3K)-like kinases (PIKKs) such as TOR and SMG1. PIKK stabilization depends on an additional complex of TELO2, TTI1, and TTI2 (TTT), whose structure and function are poorly understood. The cryoelectron microscopy (cryo-EM) structure of the human R2TP-TTT complex, together with biochemical experiments, reveals the mechanism of TOR recruitment to the R2TP-TTT chaperone. The HEAT-repeat TTT complex binds the kinase domain of TOR, without blocking its activity, and delivers TOR to the R2TP chaperone. In addition, TTT regulates the R2TP chaperone by inhibiting RUVBL1-RUVBL2 ATPase activity and by modulating the conformation and interactions of the PIH1D1 and RPAP3 components of R2TP. Taken together, our results show how TTT couples the recruitment of TOR to R2TP with the regulation of this chaperone system.

LINK a la publicación.

A molecular view of DNA flexibility

No te pierdas la revisión del grupo de nuestro coordinador Fernando Moreno-Herrero sobre los conocimientos que se pueden obtener de las propiedades mecánicas del DNA con experimentos de molécula única y simulaciones de dinámica molecular.

Continue Reading