Mechanistic insight into the interactions of NAP1 with NDP52 and TAX1BP1 for the recruitment of TBK1

Abstract

NDP52 and TAX1BP1, two SKICH domain-containing autophagy recetpors, play crucial roles in selective autophagy. The autophagic functions of NDP52 and TAX1BP1 are regulated by TBK1, which can indirectly associate with them through the adaptor protein NAP1. However, the molecular mechanism governing the interactions of NAP1 with NDP52 and TAX1BP1 as well as the effects induced by TBK1-mediated phosphorylation of NDP52 and TAX1BP1 remain elusive. Here, we reported the first atomic structures of the SKICH regions of NDP52 and TAX1BP1 in complex with NAP1, which not only uncover the mechanismtic basis underpinning the specific interactions of NAP1 with NDP52 and TAX1BP1, but also reveal the first binding mode of a SKICH domain. Moreover, we demonstrated that the phosphorylation of TAX1BP1 SKICH mediated by TBK1 may regulate the interaction between TAX1BP1 and NAP1. In all, our findings provide mechanistic insights into the NAP1-mediated recruitments of TBK1 to NDP52 and TAX1BP1, and are valuable for further understanding the functions of these proteins in selective autophagy.