NDP52

NDP52, also known as nuclear dot protein 52 kDa, is a cytosolic autophagy receptor that mediates selective autophagy. It recognizes ubiquitinated cargo, such as intracellular bacteria and damaged organelles, and links them to the autophagy machinery for degradation in autophagosomes. In this context, NDP52 participates in xenophagy and mitophagy, contributing to cellular quality control and innate immune defense.

Discovery and gene information: NDP52 was originally identified as a nuclear dot–associated protein, but it is now recognized for its role in autophagy. The human gene CALCOCO2 encodes the NDP52 protein. The protein is conserved across vertebrates and functions as part of the broader network of selective autophagy receptors.

Structure and domains: NDP52 contains features that support cargo recognition and autophagosome recruitment, including an N-terminal region that assists membrane interactions, a central coiled-coil domain, and a C-terminal region that provides ubiquitin-binding capacity and an LC3-interacting region (LIR). The LIR enables direct binding to LC3 family proteins on autophagosomes, while the ubiquitin-binding region allows recognition of polyubiquitinated cargo. These domains enable coordinated cargo selection and delivery to the autophagy machinery.

Function and interactions: By binding ubiquitinated cargo and LC3 on autophagosomes, NDP52 promotes sequestration of cargo into autophagosomes and subsequent degradation. It operates in concert with other autophagy receptors, such as OPTN and NBR1, and its function can be modulated by signaling pathways that regulate autophagy.

Regulation and significance: TBK1 kinase phosphorylates NDP52, enhancing its activity in selective autophagy. As part of the autophagy network, NDP52 contributes to host defense and cellular homeostasis. Dysregulation of selective autophagy receptors, including NDP52, has been linked to inflammatory responses and neurodegenerative processes in some contexts.