ATE1-mediated post-translational addition of arginine to a protein has been shown to regulate activity, interaction, and stability of the protein substrates. Arginylation has been linked to many different stress conditions, namely ER stress, cytosolic misfolded protein stress, and nitrosative stress. However, clear understanding about the effect of arginylation in cellular stress responses is yet to emerge. In this study, we investigated the role of arginylation in heat-stress response. Our findings suggest that Ate1 knock out (KO) cells are more susceptible to heat stress compared with its wild-type counterparts due to the induction of apoptosis in KO cells. Gene expression analysis of inducible heat-shock proteins (HSP70.1, HSP70.3, and HSP40) showed induction of these genes in KO cells early in the heat shock, but were drastically diminished at the later period of heat shock. Further analysis revealed that loss of ATE1 drastically reduced the stability of all three HSP mRNAs. These phenotypes were greatly restored by overexpression of Ate1 in KO cells. Our findings show that arginylation plays a protective role during heat stress by regulating HSP gene expression and mRNA stability.
The NF-κB signalling pathway is a major signalling cascade involved in the regulation of inflammation and innate immunity. It is also increasingly recognised as a crucial player in many steps of cancer initiation and progression. The five members of the NF-κB family of transcription factors are activated through two major signalling pathways, the canonical and non-canonical pathways. The canonical NF-κB pathway is prevalently activated in various human malignancies as well as inflammation-related disease conditions. Meanwhile, the significance of non-canonical NF-κB pathway in disease pathogenesis is also increasingly recognized in recent studies. In this review, we discuss the double-edged role of the NF-κB pathway in inflammation and cancer, which depends on the severity and extent of the inflammatory response. We also discuss the intrinsic factors, including selected driver mutations, and extrinsic factors, such as tumour microenvironment and epigenetic modifiers, driving aberrant activation of NF-κB in multiple cancer types. We further provide insights into the importance of the interaction of NF-κB pathway components with various macromolecules to its role in transcriptional regulation in cancer. Finally, we provide a perspective on the potential role of aberrant NF-κB activation in altering the chromatin landscape to support oncogenic development.
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