bioRxiv Science⌕ Search

Biology subjects

Markazi, A.

Publications and source records attributed to Markazi, A..

2 recordsLinked to original sources
bioRxiv2022

N6-methyladenosine (m6A) and reader protein YTHDF2 enhance innate immune response by mediating DUSP1 mRNA degradation and activating mitogen-activated protein kinases during bacterial and viral infections

Mitogen-activated protein kinases (MAPKs) play critical roles in the induction of numerous cytokines, chemokines, and inflammatory mediators that mobilize the immune system to counter pathogenic infections. Dual-specificity phosphatase-1 (DUSP1) is a member of dual-specificity phosphatases, which inactivates MAPKs through a negative feedback mechanism. Here we report that in response to viral and bacterial infections, not only DUSP1 transcript but also its N6-methyladenosine (m6A) level rapidly increase together with the m6A reader protein YTHDF2, resulting in enhanced YTHDF2-mediated DUSP1 transcript degradation. Knockdown of DUSP1 promotes p38 and JNK phosphorylation and activation, thus increasing the expression of innate immune response genes including IL1{beta}, CSF3, TGM2 and SRC. Similarly, knockdown of m6A eraser ALKBH5 increases DUSP1 transcript m6A level resulting in accelerated transcript degradation, activation of p38 and JNK, and enhanced expression of IL1{beta}, CSF3, TGM2 and SRC. These results demonstrate that m6A and reader protein YTHDF2 orchestrate optimal innate immune response during viral and bacterial infections by downregulating the expression of a negative regulator DUSP1 of the p38 and JNK pathways that are central to innate immune response against pathogenic infections. IMPORTANCEInnate immunity is central for controlling pathogenic infections and maintaining the homeostasis of the host. In this study, we have revealed a novel mechanism regulating innate immune response during viral and bacterial infections. We have found that N6-methyladenosine (m6A) and the reader protein YTHDF2 regulate dual-specificity phosphatase-1, a negative regulator of mitogen-activated protein kinases p38 and JNK, to maximize innate immune response during viral and bacterial infections. These results provide novel insights into the mechanism regulating innate immunity, which could help the development of novel approaches for controlling pathogenic infections.

microbiology↗
bioRxiv2020

Pseudomonas aeruginosa Stimulates Inflammation and Enhances KSHV-Induced Cell Proliferation and Cellular Transformation through Both LPS and Flagellin

Inflammation triggered by innate immunity promotes carcinogenesis in cancer. Kaposis sarcoma (KS), a hyperproliferative and inflammatory tumor caused by Kaposis sarcoma-associated herpesvirus (KSHV) infection, is the most common cancer in AIDS patients. KSHV infection sensitizes cells to pathogen-associated molecular patterns (PAMPs). We examined the role of Pseudomonas aeruginosa (PA), an opportunistic bacterium that can affect AIDS patients, in inflammation and cell proliferation of KSHV-transformed cells. PA stimulation increased cell proliferation and efficiency of colony formation in softagar of KSHV-transformed rat primary mesenchymal precursor (KMM) cells but had no significant effect on the untransformed (MM) cells. PA stimulation also increased cell proliferation of KSHV-infected human B-cells, Bjab, but not the uninfected cells. Mechanistically, PA stimulation resulted in increased inflammatory cytokines and activation of p38, ERK1/2, and JNK mitogen-activated protein kinase (MAPK) pathways in KMM cells while having no obvious effect on MM cells. PA induction of inflammation and MAPKs were observed with and without inhibition of Toll-like receptor 4 (TLR4) pathway while a flagellin-deleted mutant of PA required a functional TLR4 pathway to induce inflammation and MAPKs. Furthermore, treatment with both LPS or flagellin alone was sufficient to induce inflammatory cytokines, activate MAPKs, and increase cell proliferation and efficiency of colony formation in softagar of KMM cells. These results demonstrate that both LPS and flagellin are PAMPs that contribute to PA induction of inflammation in KSHV-transformed cells. Because AIDS-KS patients are susceptible to PA infection, our work highlights the preventive and therapeutic potential of targeting PA infection in these patients. ImportanceKaposis sarcoma (KS), caused by infection of Kaposis sarcoma-associated herpesvirus (KSHV), is one of the most common cancers in AIDS patients. KS is a highly inflammatory tumor but how KSHV infection induces inflammation remains unclear. We have previously shown that KSHV infection upregulates Toll-like receptor 4 (TLR4), sensitizing cells to lipopolysaccharide (LPS) and Escherichia coli. In the current study, we examined the role of Pseudomonas aeruginosa (PA), an opportunistic bacterium that can affect AIDS patients, in inflammation and cell proliferation of KSHV-transformed cells. PA stimulation increased cell proliferation, inflammatory cytokines, and activation of growth and survival pathways in KSHV-transformed cells through two pathogen-associated molecular patterns LPS and flagellin. Because AIDS-KS patients are susceptible to PA infection, our work highlights the preventive and therapeutic potential of targeting PA infection in these patients.

cancer biology↗