Although cadmium (Cd)‐induced hepatoxicity is well established, pronounced knowledge gaps remain existed regarding the inherent cellular signaling that dictates Cd toxicity. Specifically, the molecular basis for determining the equilibrium between prosurvival and proapoptotic signaling remains poorly understood. Thus, it is recently revealed that long non‐coding RNA (lncRNA) MT1DP, a pseudogene in the metallothionein (MT) family, promoted Cd‐induced cell death through activating the RhoC‐CCN1/2‐AKT pathway and modulating MT1H induction. Here, first the dependency of MT1DP induction on MTF1, an important transcriptional factor in driving the mRNA expression of MT1 members is defined. Additionally, a bridge molecule between MT1DP and nuclear factor erythroid 2‐related factor 2 (Nrf2) is established: miR‐365. Mechanistically, MT1DP induction under Cd stress decreases the nuclear factor erythroid 2‐related factor 2 (Nrf2) level to evoke oxidative stress through the elevation of miR‐365, which acted to repress the Nrf2 level via direct binding to its 3'UTR. In contrast to the competing endogenous RNA (ceRNA) mechanism, a new mechanism is proposed: MT1DP elevated the miR‐365 level though stabilizing its RNA via direct binding. Collectively, the combined data demonstrate a crucial role of MT1DP in reducing the Nrf2‐mediated protection of cells, and this is dependent on the interplay with miR‐365. Hence, the study further expands the knowledge of inducible endogenous lncRNA in modulating oxidative stress.
Hepatic inflammation is the driving force for the development and progression of NASH. Treatment targeting inflammation is believed to be beneficial. In this study, adoptive transfer of CD4+ T cells converted double negative T cells (cDNT) protects mice from diet-induced liver fat accumulation, lobular inflammation and focal necrosis. cDNT selectively suppress liver-infiltrating Th17 cells and proinflammatory M1 macrophages. IL-10 secreted by M2 macrophages decreases the survival and function of cDNT to protect M2 macrophages from cDNT-mediated lysis. NKG2A, a cell inhibitory molecule, contributes to IL-10 induced apoptosis and dampened suppressive function of cDNT. In conclusion, ex vivo-generated cDNT exert potent protection in diet induced obesity, type 2 diabetes and NASH. The improvement of outcome is due to the inhibition on liver inflammatory cells. This study supports the concept and the feasibility of potentially utilizing this autologous immune cell-based therapy for the treatment of NASH.
Metallothioneins (MTs) are known to protect cells against oxidative stress, especially providing protection against cadmium (Cd) toxicity in hepatocytes. There are various gene variants and pseudogenes for MTs; however, there is little understanding on the functions of those non-coding MT members that are known to be expressed as long non-coding RNAs (lncRNAs) nowadays. Different from most protein-coding MT members, MT1DP was here found that remarkably induced to provoke cytotoxicity in hepatocytes in response to Cd treatment. MT1DP exerted such a pro-apoptotic function in Cd-treated hepatocytes through interacting with two partners: RhoC and MT1H. On one hand, MT1DP interacted with RhoC protein to increase the latter’s stability by preventing lysosome-dependent protein degradation. Therefore, upon Cd stress, MT1DP/RhoC complex was quickly reinforced to activate RhoC-CCN1/2-AKT signaling and potentiate Ca2+ influx, leading to enhanced Cd uptake and elevated Cd toxicity. On the other hand, MT1H, a protein-coding member of the MT family with little known function, was found to quickly respond to Cd exposure along with MT1DP. Mechanistically, MT1H and MT1DP were uncovered to mutually protect each other through a reciprocal ceRNA mechanism, building up a positive feedback loop to enforce MT1DP-conducted signaling upon Cd exposure. Moreover, MT1DP was found to contribute much more to the activation of RhoC-CCN1/2-AKT signaling than MT1H. Considered together, we here unveiled a mystery whether a pseudogene within the MT family, MT1DP, has actual biological functions in regulating Cd-induced cellular defense. Our findings unearthed an important role of pseudogene MT1DP in calibrating the cellular machinery to switch the cellular defense to cytotoxicity through crosslinking an interplay between its two partners, namely MT1H and RhoC, under cadmium stress.
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