Humaira Ilyas

NPM1-mutated acute myeloid leukemia (AML) is defined by aberrant cytoplasmic localization of the mutant NPM1c protein, and therapeutic strategies targeting this specific disease remain limited. Here, we identify TTLL4, a mono-glutamate glutamyltransferase, as a selective vulnerability in NPM1c AML. TTLL4 catalyzes post-translational hyper-glutamylation of NPM1c at E126, stabilizes its cytoplasmic localization and promotes a differentiation block in leukemic cells. Multiple genetic TTLL4 inactivation approaches in human NPM1c-mutant cell lines reduce NPM1c glutamylation, trigger myeloid differentiation, and impair proliferation. Transcriptomic analyses show that TTLL4 knockdown pheno-copies NPM1c degradation and aligns with KMT2A and XPO1-targeted gene expression programs. Furthermore, Ttll4 knockout significantly prolonged survival in an NPM1c/NRAS-driven mouse AML model and promoted differentiation. We identify a small molecule, EN7, that selectively inhibits TTLL4 and recapitulates these phenotypes in NPM1c ⁺ cells. These findings identify glutamylation as a new axis of leukemic regulation and highlight TTLL4 as a druggable epigenetic regulator in NPM1c AML.

The article titled “The Efficacy of Copper Nanoparticles in Treating Viral Skin Infections: A Systematic Review and Meta-Analysis” by Hassan et. al. cannot be considered for publication in its current state. The article has various major issues, con...

Histone chaperones–structurally diverse, non-catalytic proteins enriched with acidic intrinsically disordered regions (IDRs)–protect histones from spurious nucleic acid interactions and guide their deposition into and out of nucleosomes. Despite their conservation and ubiquity, the function of the chaperone acidic IDRs remains unclear. Here, we show that the Xenopus laevis Npm2 and Nap1 acidic IDRs are substrates for TTLL4 (Tubulin Tyrosine Ligase Like 4)-catalyzed post-translational glutamate-glutamylation. We demonstrate that, to bind, stabilize, and deposit histones into nucleosomes, chaperone acidic IDRs function as DNA mimetics. Our biochemical, computational, and biophysical studies reveal that glutamylation of these chaperone polyelectrolyte acidic stretches functions to enhance DNA electrostatic mimicry, promoting the binding and stabilization of H2A/H2B heterodimers and facilitating nucleosome assembly. This discovery provides insights into both the previously unclear function of the acidic IDRs and the regulatory role of post-translational modifications in chromatin dynamics.

Antimicrobial peptides have gained widespread attention as an alternative to the conventional antibiotics for combating microbial infections. Here, we report a detailed structure-function correlation of two non-toxic, non-hemolytic and salt tolerant de novo designed seven-residue leucine-lysine based peptides, NH2LKWLKKLCONH2 (P4) and NH2LRWLRRLCONH2 (P5), with strong antimicrobial and antifungal activity. Biological experiments, low- and high-resolution spectroscopic techniques in conjunction with molecular dynamics simulation studies, could establish the structure-function correlation. The peptides are unstructured both in water as well as in bacterial membrane mimicking environment, suggesting that the secondary structure does not play a major role in their activity. Our studies could justify the probable membranolytic mode of action for killing the pathogens. Attempts of understanding the mode of action of these small AMPs is fundamental in rational design of more such potential therapeutic molecules beyond serendipity in the future.