Lysine fatty acylation promotes lysosomal targeting of TNF-α

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammation cytokine secreted by various cells. Understanding its secretive pathway is important to understand the biological functions of TNF-alpha and diseases associated with TNF-alpha. TNF-alpha is one of the first proteins known be modified by lysine fatty acylation (e.g. myristoylation). We previously demonstrated that SIRT6, a member of the mammalian sirtuin family of enzymes, can remove the fatty acyl modification on TNF-alpha and promote its secretion. However, the mechanistic details about how lysine fatty acylation regulates TNF-alpha secretion have been unknown. Here we present experimental data supporting that lysine fatty acylation promotes lysosomal targeting of TNF-alpha. The result is an important first step toward understanding the biological functions of lysine fatty acylation.