MDA5

Abstract: Drug design in aggressive cancers such as melanoma is challenged by a heterogeneous histopathology and the acquisition of a plethora of genetic and epigenetic alterations. Drug pumps, detoxification mechanisms, defects in programmed forms of cell death, and activation of survival mechanisms contribute to resistance to standard therapeutic agents. Here we describe the identification and functional validation of BO-110, a new double-stranded (ds)RNA-based nanocomplex that we found as a potent anti-cancer agent in vivo. First tested in melanoma cells, BO-110 was found to induce a tumor-cell selective killing by a combined activation of autophagy and apoptosis, in part via the innate immunity sensor Melanoma Differentiation-Associated gene-5 (MDA5), a cytosolic dsRNA helicase. A key effector of the innate responses by BO-110 is the pro-apoptotic protein NOXA, which this compound induces in a manner not recapitulated by classical chemo or immunotherapeutic agents. Importantly, BO-110 is highly effective against a broad spectrum of cancer types, while maintaining the viability of normal cells of different lineages. Therefore, dsRNA nanoplexes promote a combined activation of RNA helicases, autophagy, and apoptosis that can be exploited therapeutically in otherwise highly resistant human cancers.

Abstract: Abstract Leukemia initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches to eliminate LICs and prevent relapse. Here, we show that the RNA editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine (A-to-I) editing is a common attribute of relapsed T-ALL regardless of molecular subtypes. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL PDX models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA and retains unedited nuclear dsRNA to avoid detection by the innate immune sensor MDA5. Moreover, we uncovered that the cell intrinsic level of MDA5 dictates the dependency on ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents a safe and effective therapeutic strategy for eliminating T-ALL LICs.

Abstract: Background and objectives: Melanoma differentiation‐associated gene 5 antibody (anti‐MDA5) in dermatomyositis (DM) is associated with rapidly progressive interstitial lung disease and poor prognosis. Early diagnosis is key to improving the prognosis of these patients. The aim was to confirm cutaneous characteristics in patients with anti‐MDA5 dermatomyositis and to explore new diagnostic markers for the presence of anti‐MDA5 (anti‐MDA5+).

Abstract: 1. Melanoma differentiation-associated gene 5 (MDA5) is a critical member of cytosolic pattern recognition receptors (PRRs) that recognise viral RNA and mediate type I interferon secretion in host cells. 2. The objective of the present study was to identify and characterise the structure and expression of pigeon MDA5. 3. The full-length MDA5 cDNA was cloned from pigeon spleen using RT-PCR and RACE. The distribution and expression level of pigeon MDA5 in different tissues were determined by QRT-PCR. 4. The results showed that the full-length pigeon MDA5 cDNA had 3858 nucleotides (containing a 210-bp 5'-UTR, a 3030-bp open reading frame and a 618-bp 3'-UTR) encoding a polypeptide of 1009 amino acids. The deduced amino acid sequence contained six conserved structural domains typical of RIG-I-like receptor (RLR), including two tandem arranged N-terminal caspase activation and recruitment domains (CARDs), a DEAH/DEAD box helicase domain (DExDc), a helicase superfamily c-terminal domain (HELICc), a type III restriction enzyme (ResIII) and a C-terminal regulatory domain (RD). 5. The pigeon MDA5 showed 84.8%, 87.3%, 87.9% and 87.2% amino acid sequence identities with previously described homologues from chicken, duck, goose and Muscovy ducks, respectively, and phylogenetic analysis revealed a close relationship among these MDA5. 6. Pigeon MDA5 transcript was ubiquitously expressed in all seven tissues tested in healthy pigeons and showed a high level in the thymus gland and kidney. 7. These findings lay the foundation for further research on the function and mechanism of MDA5 in innate immune responses related to vaccinations and infectious diseases in the pigeon.