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Abstract Zinc (Zn) is an essential trace element that modulate innate and acquired immune responses, and its deficiency triggers lymphopenia. However, the precise mechanisms underlying zinc-mediated lymphocyte maintenance have not been well clarified. Here, we have successfully generated a zip6 -null mutant zebrafish line using TALENs. The Zip6 -null mutant zebrafish developed normally during gastrulation. Loss of zip6 in zebrafish resulted in significant T lymphocyte reduction and a decrease in intracellular Zn levels. And the zip6 deficiency increases caspase-related cell apoptosis in both zebrafish cells and human T cells. Our results suggest that ZIP6 plays a critical part in T cell development, and enhance our understanding of Zn homeostasis and immune system maintenance. Highlights • Generate a zip6 -null mutant zebrafish line using TALENs. • Loss of zip6 in zebrafish results in significant T lymphocyte reduction. • Zip6 deficiency increases caspase-related cell apoptosis. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic malignancy with poor survival and frequent relapse. Recently, a posttranslational modification of proteins with small ubiquitin-like modifiers (SUMO) has been notably implicated in a wide spectrum of diseases, especially cancers. Ubc9, as the sole E2-conjugating enzyme in SUMOylation cascade, particularly has been associated with adverse clinical outcomes. 2-D08, a small molecular agent, functions by blocking the transfer of SUMO from the Ubc9 thioester to SUMO substrates without any effects on other individual steps in this process. However, both the effects and mechanisms of 2-D08 on AML cells are still unknown. In this study, we found that 2-D08 significantly suppressed cell viability and colony formation ability. Additionally, it induced mitochondrial-mediated apoptosis with dramatic accumulation of the reactive oxygen species (ROS), which could be almost completely rescued by the ROS scavenger N -acetylcysteine (NAC). Furthermore, we confirmed that the fatal accumulation of ROS was due to its aberrant generation instead of defective scavenging. In summary, our results suggest that 2-D08, as a specific SUMOylation inhibitor, induces ROS accumulation-mediated intrinsic apoptosis of AML cells possibly through deSUMOylation of NOX2. Therefore, 2-D08 might be a promising therapeutic agent for the treatment of AML in the future. Image 1 • 2-D08 inhibits the cell viability, colony formation ability and provokes apoptosis of AML cells. • 2-D08 induces the mitochondria-mediated apoptosis in AML cells. • Aberrant accumulation of ROS is required for 2-D08 induced apoptosis in AML cells. • NADPH oxidases up-regulation and NOX2 deSUMOylation might be key events in 2-D08 induced ROS accumulation in AML cells. [ABSTRACT FROM AUTHOR]