The helicase protein DHX29 promotes translation initiation, cell proliferation, and tumorigenesis

Translational control plays an important role in cell growth and tumorigenesis. Cap-dependent translation initiation of mammalian mRNAs with structured 5′UTRs requires the DExH-box protein, DHX29, in vitro. Here we show that DHX29 is important for translation in vivo. Down-regulation of DHX29 leads to impaired translation, resulting in disassembly of polysomes and accumulation of mRNA-free 80S monomers. DHX29 depletion also impedes cancer cell growth in culture and in xenografts. Thus, DHX29 is a bona fide translation initiation factor that potentially can be exploited as a target to inhibit cancer cell growth

Inhibition of the membrane repair protein annexin-A2 prevents tumour invasion and metastasis

Abstract Cancer cells are exposed to major compressive and shearing forces during invasion and metastasis, leading to extensive plasma membrane damage. To survive this mechanical stress, they need to repair membrane injury efficiently. Targeting the membrane repair machinery is thus potentially a new way to prevent invasion and metastasis. We show here that annexin-A2 (ANXA2) is required for membrane repair in MDA-MB-231 cells, a highly invasive triple-negative breast cancer cell line. Mechanistically, we show by fluorescence and electron microscopy that cells fail to reseal membrane damaged by shear stress when ANXA2 is silenced or the protein is inhibited with neutralizing antibody. Silencing of ANXA2 has no effect on proliferation in vitro, and even accelerates migration in wound healing assays, but reduces tumor cell dissemination in both mice and zebrafish. We show that high expression of ANXA2 predicts poor prognosis in high-grade lung, ovarian, gastric and breast cancers. We expect that inhibiting membrane repair will be particularly effective in these aggressive, poor prognosis tumors because they rely on the membrane repair machinery to survive membrane damage during tumor invasion and metastasis. This could be achieved either with monoclonal anti-ANXA2 antibodies, which have been shown to inhibit metastasis of MDA-MB-231 cells, or with small molecule drugs.Les cellules cancéreuses sont exposées à d'importantes forces de compression et de cisaillement lors de l'invasion et de la formation de métastases, ce qui entraîne des lésions importantes de la membrane plasmique. Pour survivre à ce stress mécanique, elles doivent réparer efficacement les lésions membranaires. Cibler la machinerie de réparation de la membrane est donc potentiellement un nouveau moyen de prévenir l'invasion et les métastases. Nous montrons ici que l'annexine-A2 (ANXA2) est nécessaire à la réparation de la membrane dans les cellules MDA-MB-231, une lignée cellulaire de cancer du sein triplégique très invasive. Sur le plan mécanique, nous montrons par fluorescence et microscopie électronique que les cellules ne parviennent pas à refermer la membrane endommagée par la contrainte de cisaillement lorsque l'ANXA2 est réduite au silence ou que la protéine est inhibée à l'aide d'un anticorps neutralisant. L'inhibition d'ANXA2 n'a aucun effet sur la prolifération in vitro, et accélère même la migration dans les essais de cicatrisation, mais réduit la dissémination des cellules tumorales chez la souris et le poisson zèbre. Nous montrons qu'une forte expression d'ANXA2 prédit un mauvais pronostic dans les cancers du poumon, de l'ovaire, de l'estomac et du sein de haut grade. Nous pensons que l'inhibition de la réparation membranaire sera particulièrement efficace dans ces tumeurs agressives et de mauvais pronostic, car elles dépendent de la machinerie de réparation membranaire pour survivre aux lésions membranaires lors de l'invasion tumorale et de la formation de métastases. Cet objectif pourrait être atteint soit à l'aide d'anticorps monoclonaux antiANXA2, qui se sont révélés capables d'inhiber les métastases des cellules MDA-MB-231, soit à l'aide de médicaments à petites molécules

Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

International audienc

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old