• Aminoacyl-tRNA synthetases (AARSs) of multi-tRNA synthetase complex (MSC) are involved in cancer pathogenesis. • The scaffolding proteins of MSC have mainly anti-tumorigenic functions whereas the MSC associated AARSs have pro-tumorigenic roles. • MSC release of AARSs is a pre-requisite for performing non-canonical functions related to cancer pathogenesis. • MSC associated AARSs and the auxiliary proteins can provide novel therapeutic modalities against cancer.

The occurrence of DNA architectural proteins containing two functional domains derived from two different architectural proteins is an interesting emerging research theme in the field of nucleoid structure and function. Mycobacterium tuberculosis HupB, unlike Escherichia coli HU, is a two‐domain protein that, in the N‐terminal region, shows broad sequence homology with bacterial HU. The long C‐terminal extension, on the other hand, contains seven PAKK/KAAK motifs, which are characteristic of the histone H1/H5 family of proteins. In this article, we describe several aspects of HupB function, in comparison with its truncated derivatives lacking either the C‐terminus or N‐terminus. We found that HupB binds a variety of DNA repair and replication intermediates with K_d values in the nanomolar range. By contrast, the N‐terminal fragment of M. tuberculosis HupB (HupB_MtbN) showed diminished DNA‐binding activity, with K_d values in the micromolar range, and the C‐terminal domain was completely devoid of DNA‐binding activity. Unlike HupB_MtbN, HupB was able to constrain DNA in negative supercoils and introduce negative superhelical turns into relaxed DNA. Similarly, HupB exerted a robust inhibitory effect on DNA strand exchange promoted by cognate and noncognate RecA proteins, whereas HupB_MtbN, even at a 50‐fold molar excess, had no inhibitory effect. Considered together, these results suggest that synergy between the N‐terminal and C‐terminal domains of HupB is essential for its DNA‐binding ability, and to modulate the topological features of DNA, which has implications for processes such as DNA compaction, gene regulation, homologous recombination, and DNA repair.Structured digital abstract hupB binds to hupB by cross‐linking study (View interaction)

Ezrin links the cytoskeleton to cell surface integrins and plasma membrane receptors, contributing to the proliferative and metastatic potential of cancer cells. Elevated ezrin expression in several cancers is associated with poor outcomes. Tumor cell ezrin expression and function have been investigated in depth; however, its role in macrophages and other tumor microenvironment cells remains unexplored. Macrophages profoundly influence tumorigenesis, and here we explore ezrin’s influence on tumor-promoting macrophage functions. Ezrin knockdown in THP-1 macrophages reveals its important contribution to adhesion to endothelial cells. Unexpectedly, ezrin is essential for the basal and breast cancer cell-stimulated THP-1 expression of ITGAM mRNA that encodes integrin CD11b, critical for cell adhesion. Ezrin skews the differentiation of THP-1 macrophages towards the pro-tumorigenic, M2 subtype, as shown by the reduced expression of FN1, IL10, and CCL22 mRNAs following ezrin knockdown. Additionally, macrophage ezrin contributes to the secretion of factors that stimulate tumor cell migration, invasion, and clonogenic growth. Lastly, THP-1 ezrin is critical for the expression of mRNAs encoding vascular endothelial growth factor (VEGF)-A and matrix metalloproteinase (MMP)-9, consistent with pro-tumorigenic function. Collectively, our results provide insight into ezrin’s role in tumorigenesis, revealing a bidirectional interaction between tumor-associated macrophages and tumor cells, and suggest myeloid cell ezrin as a target for therapeutic intervention against cancer.