Biology subjects

Morel, M.

Publications and source records attributed to Morel, M..

4 recordsLinked to original sources

bioRxiv2021

Conditional ERK3 overexpression cooperates with PTEN deletion to promote lung adenocarcinoma formation in mice

Extracellular signal-regulated kinase 3 (ERK3), also known as MAPK6, belongs to the atypical mitogen-activated protein kinases (MAPKs) subfamily. In comparison with the well-studied classical MAPKs ERK1 and ERK2, much less is known about the cellular and molecular actions of ERK3. Accumulating studies have revealed the upregulation of ERK3 expression and suggested an important role for ERK3 in promoting tumor cell growth and invasion in multiple cancers, in particular lung cancer. However, it is unknown whether or not ERK3 plays a role in spontaneous tumorigenesis. To determine the role of ERK3 in lung tumorigenesis, we created a conditional ERK3 transgenic mouse line in which ERK3 transgene expression is controlled by Cre recombinase. By crossing with a lung tissue-specific CCSP-iCre mouse line, we have found that conditional ERK3 overexpression cooperates with PTEN deletion to induce the formation of lung adenocarcinomas (LUADs). Mechanistically, ERK3 overexpression stimulates activating phosphorylations of ERBB3 and ERBB2 by upregulating SP1-mediated gene transcription of NRG1, a potent ligand for ERBB3/ERBB2. To our knowledge, our study is the first revealing a bona fide tumor-promoting role for ERK3 using genetically engineered mouse models. Together with previous findings showing important roles of ERK3 in cultured cells and in xenograft lung tumor model, our findings corroborate that ERK3 acts as an oncoprotein in promoting LUAD development and progression.

cancer biology↗

bioRxiv2021

Sensitive Detection of Site-wise Convergent Evolution in Large Protein Alignments with ConDor

Evolutionary convergences are observed at all levels, from phenotype to DNA and protein sequences, and changes at these different levels tend to be highly correlated. Notably, convergent and parallel mutations can lead to convergent changes in phenotype, such as changes in metabolism, drug resistance, and other adaptations to changing environments. We propose a two-step approach to detect mutations under convergent evolution in protein alignments. We first select mutations that emerge more often than expected under neutral evolution and then test whether their emergences correlate with the convergent phenotype under study. The first step can be used alone when no phenotype is available, as is often the case with microorganisms. In the first step, a phylogeny is inferred from the data and used to simulate the evolution of each alignment position. These simulations are used to estimate the expected number of mutations under neutral conditions, which is compared to what is observed in the data. Next, using a comparative phylogenetic approach, we measure whether the presence of mutations occurring more often than expected correlates with the convergent phenotype. Our method is implemented in a standalone workflow and a webserver, called ConDor. We apply ConDor to three datasets: sedges PEPC proteins, HIV reverse transcriptase and fish rhodopsin. The results show that the two components of ConDor complement each other, with an overall accuracy that compares favorably to other available tools, especially on large datasets.

evolutionary biology↗

bioRxiv2021

Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx

Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) succeed to evade host immune defenses by using their viral auxiliary proteins to antagonize host restriction factors. HIV-2/SIVsmm Vpx is known for degrading SAMHD1, a factor impeding the reverse transcription. More recently, Vpx was also shown to counteract HUSH, a complex constituted of TASOR, MPP8 and periphilin, which blocks viral expression from the integrated viral DNA. In a classical ubiquitin ligase hijacking model, Vpx bridges the DCAF1 ubiquitin ligase substrate adaptor to SAMHD1, for subsequent ubiquitination and degradation. Here, we investigated whether the same mechanism is at stake for Vpx-mediated HUSH degradation. While we confirm that Vpx bridges SAMHD1 to DCAF1, we show that TASOR can interact with DCAF1 in the absence of Vpx. Nonetheless, this association was stabilized in the presence of Vpx, suggesting the existence of a ternary complex. The N-terminal PARP-like domain of TASOR is involved in DCAF1 binding, but not in Vpx binding. We also characterized a series of HIV-2 Vpx point mutants impaired in TASOR degradation, while still degrading SAMHD1. Vpx mutants ability to degrade TASOR correlated with their capacity to enhance HIV-1 minigenome expression as expected. Strikingly, several Vpx mutants impaired for TASOR degradation, but not for SAMHD1 degradation, had a reduced binding affinity for DCAF1, but not for TASOR. In macrophages, Vpx R34A-R42A and Vpx R42A-Q47A-V48A, strongly impaired in DCAF1, but not in TASOR binding, could not degrade TASOR, while being efficient in degrading SAMHD1. Altogether, our results highlight the central role of a robust Vpx-DCAF1 association to trigger TASOR degradation. We then propose a model in which Vpx interacts with both TASOR and DCAF1 to stabilize a TASOR-DCAF1 complex. Furthermore, our work identifies Vpx mutants enabling the study of HUSH restriction independently from SAMHD1 restriction in primary myeloid cells. Author SummaryHuman Immunodeficiency Virus (HIV) is still a major public health issue. The understanding of the molecular battle occurring during viral infection, between HIV components and cellular antiviral factors, the so-called restriction factors, is a key determinant for new treatment development. Namely, HIV auxiliary proteins are powerful to induce the downregulation of cellular restriction factors by hijacking the Ubiquitin-Ligase/proteasome pathway, in order to facilitate the completion of a well-processed HIV replication cycle. For instance, HIV-2 Vpx eases reverse transcription in myeloid cells by counteracting the SAMDH1 restriction factor. More recently, we discovered the ability of Vpx to induce the degradation of the HUSH epigenetic repressor complex to favor in turn, the expression of the provirus. In this study, we uncovered the mechanisms by which Vpx antagonizes TASOR, the core subunit of the HUSH complex. We highlighted key differences between Vpx-induced TASOR and SAMHD1 degradation. These findings will help to propose strategies to study or to target either HUSH or SAMHD1, especially in myeloid cells where the two restriction factors coexist.

microbiology↗

bioRxiv2020

TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV

The Human Silencing Hub (HUSH) complex constituted of TASOR, MPP8 and Periphilin is involved in the spreading of H3K9me3 repressive marks across genes and transgenes such as ZNF encoding genes, ribosomal DNAs, LINE-1, Retrotransposons and Retroelements or the integrated HIV provirus1-5. The deposit of these repressive marks leads to heterochromatin formation and inhibits gene expression. The precise mechanisms of silencing mediated by HUSH is still poorly understood. Here, we show that TASOR depletion increases the accumulation of transcripts derived from the HIV-1 LTR promoter at a post-transcriptional level. By counteracting HUSH, Vpx from HIV-2 mimics TASOR depletion. With the use of a Yeast-Two-Hybrid screen, we identified new TASOR partners involved in RNA metabolism including the RNA deadenylase CCR4-NOT complex scaffold CNOT1. TASOR and CNOT1 interact in vivo and synergistically repress HIV expression from its LTR. In fission yeast, the RNA-induced transcriptional silencing (RITS) complex presents structural homology with HUSH. During transcription elongation by RNA polymerase II, RITS recruits a TRAMP-like RNA degradation complex composed of CNOT1 partners, MTR4 and the exosome, to ultimately repress gene expression via H3K9me3 deposit. Similarly, we show that TASOR interacts and cooperates with MTR4 and the exosome, in addition to CNOT1. We also highlight an interaction between TASOR and RNA Polymerase II, predominantly under its elongating state, and between TASOR and some HUSH-targeted nascent transcripts. Furthermore, we show that TASOR overexpression facilitates the association of the aforementioned RNA degradation proteins with RNA polymerase II. Altogether, we propose that HUSH operates at the transcriptional and post-transcriptional levels to repress HIV proviral gene expression.

molecular biology↗