Bmi1 Promotes Cholangiocarcinoma Progression And Correlates With Antitumor Immunity In An Exosome-Dependent Manner

Background: Cholangiocarcinoma (CCA) is a class of malignant tumors originating from bile duct epithelial cells. Due to difficult early diagnosis and limited treatment, the prognosis of CCA is extremely poor. Bmi1 is dysregulated in many human malignancies. However, the prognostic significance and oncogenic role of Bmi1 in cholangiocarcinoma (CCA) are not well elucidated. Methods: In the present study, we investigated its clinical importance and the potential mechanisms in the progression of CCA. We detected Bmi1 expression in a large CCA cohort. We demonstrated Bmi1 was substantially upregulated in CCA tissues and was identified as an independent prognostic biomarker of CCA. Moreover, overexpression of Bmi1 promoted CCA proliferation, migration, and invasion. And, Bmi1 knockdown could inhibit proliferation and metastases of CCA in vitro and in vitro/vivo validation. Interestingly, we found that CCA-derived exosomes contain Bmi1 proteins, which can transfer Bmi1 between CCA cells. The unique Bmi1-containing exosomes promote CCA proliferation and metastasis through autocrine/paracrine mechanisms. In addition, we demonstrated that Bmi1 inhibits CD8+T cell-recruiting chemokines by promoting repressive H2A ubiquitination in CCA cells. Conclusions: Bmi1 is an unfavorable prognostic biomarker of CCA. Our data demonstrate a novel function of Bmi1 in CCA tumorigenesis and metastasis mediated by exosomes. Besides, Bmi1 inhibition may augment immune checkpoint blockade to inhibit tumor progression by activating cell-intrinsic immunity of CCA

Regulation of Viral Restriction by Post-Translational Modifications

Intrinsic immunity is orchestrated by a wide range of host cellular proteins called restriction factors. They have the capacity to interfere with viral replication, and most of them are tightly regulated by interferons (IFNs). In addition, their regulation through post-translational modifications (PTMs) constitutes a major mechanism to shape their action positively or negatively. Following viral infection, restriction factor modification can be decisive. Palmitoylation of IFITM3, SUMOylation of MxA, SAMHD1 and TRIM5α or glycosylation of BST2 are some of those PTMs required for their antiviral activity. Nonetheless, for their benefit and by manipulating the PTMs machinery, viruses have evolved sophisticated mechanisms to counteract restriction factors. Indeed, many viral proteins evade restriction activity by inducing their ubiquitination and subsequent degradation. Studies on PTMs and their substrates are essential for the understanding of the antiviral defense mechanisms and provide a global vision of all possible regulations of the immune response at a given time and under specific infection conditions. Our aim was to provide an overview of current knowledge regarding the role of PTMs on restriction factors with an emphasis on their impact on viral replication.

Nasal Spray Vaccines – A Breath of Immunity: An Interview with Dr. Marc-André Langlois

Dr. Marc-André Langlois, a cutting-edge virologist, Canada Research Chair in Molecular Virology and Intrinsic Immunity, and Professor in the Department of Biochemistry, Microbiology and Immunology at the University of Ottawa, received 1 million dollars in Canadian Institutes of Health Research (CIHR) funding to develop a nasal spray COVID-19 vaccine. We had the privilege of meeting with him virtually and having a fascinating and informative conversation on the COVID-19 pandemic, vaccines, and its effect on society.

The Epipeptide Biosynthesis Locus epeXEPAB Is Widely Distributed in Firmicutes and Triggers Intrinsic Cell Envelope Stress

The <i>epeXEPAB</i> (formerly <i>yydFGHIJ</i>) locus of <i>Bacillus subtilis</i> encodes a minimalistic biosynthetic pathway for a linear antimicrobial epipeptide, EpeX, which is ribosomally produced and post-translationally processed by the action of the radical-SAM epimerase, EpeE, and a membrane-anchored signal 2 peptide peptidase, EpeP. The ABC transporter EpeAB provides intrinsic immunity against self-produced EpeX, without conferring resistance against extrinsically added EpeX. EpeX specifically targets, and severely perturbs the integrity of the cytoplasmic membrane, which leads to the induction of the Lia-dependent envelope stress response. Here, we provide new insights into the distribution, expression, and regulation of the minimalistic <i>epeXEPAB</i> locus of <i>B. subtilis</i>, as well as the biosynthesis and biological efficiency of the produced epipeptide EpeX*. A comprehensive comparative genomics study demonstrates that the <i>epe</i>-locus is restricted to but widely distributed within the phylum <i>Firmicutes</i>. The gene products of <i>epeXEP</i> are necessary and sufficient for the production of the mature antimicrobial peptide EpeX*. In <i>B. subtilis</i>, the <i>epeXEPAB</i> locus is transcribed from three different promoters, one upstream of <i>epeX</i> (P_<i>epeX</i>) and two within <i>epeP</i> (P_<i>epeA1</i> and P_<i>epeA2</i>). While the latter two are mostly constitutive, P_<i>epeX</i> shows a growth phase-dependent induction at the onset of stationary phase. We demonstrate that this regulation is the result of the antagonistic action of two global regulators: The transition state regulator AbrB keeps the <i>epe</i> locus shut off during exponential growth by direct binding. This tight repression is relieved by the master regulator of sporulation, Spo0A, which counteracts the AbrB-dependent repression of <i>epeXEPAB</i> expression during the transition to stationary phase. The net result of these three ­promoters is an expression pattern that ensures EpeAB-dependent autoimmunity prior to EpeX* production. In the absence of EpeAB, the general envelope stress response proteins LiaIH can compensate for the loss of specific autoimmunity by providing sufficient protection against the membrane-perturbating action of EpeX*. Hence, the transcriptional regulation of <i>epe</i> expression and the resulting intrinsic induction of the two corresponding resistance functions, encoded by <i>epeAB</i> and <i>liaIH</i>, are well balanced to provide a need-based immunity against mature EpeX*.

Elucidating the Antiviral Mechanism of Different MARCH Factors

ABSTRACT The membrane-associated RING-CH (MARCH) proteins belong to a family of E3 ubiquitin ligases, whose main function is to remove transmembrane proteins from the plasma membrane. Recent work has shown that the human MARCH1, 2, and 8 are antiretroviral factors that target the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins by reducing their incorporation in the budding virions. Nevertheless, the dearth of information regarding the antiviral mechanism of this family of proteins necessitates further examination. In this study, using both the human MARCH proteins and their mouse homologues, we provide a comprehensive analysis of the antiretroviral mechanism of this family of proteins. Moreover, we show that human MARCH proteins restrict to various degrees the envelope glycoproteins of a diverse number of viruses. This report sheds light on the important antiviral function of MARCH proteins and their significance in cell intrinsic immunity. IMPORTANCE This study examines the mechanism utilized by different MARCH proteins to restrict retrovirus infection. MARCH proteins block the incorporation of envelope glycoproteins to the budding virions. In this report, by comparing the human and mouse MARCH genes and using murine leukemia virus (MLV) and HIV-1, we identify differences in the mechanism of restriction among MARCH proteins. Furthermore, we perform a comprehensive analysis on a number of envelope glycoproteins and show that MARCH proteins have broad antiviral functions.