N4BP3

Model summary

A soluble human adaptor that assembles and positions ubiquitin-ligase signaling modules to dampen autophagy. By using multivalent protein-binding surfaces characteristic of its family, it organizes cytosolic and nuclear complexes that tune the availability and localization of NEDD4-class ligases and their partners. This spatial control reduces autophagosome formation by stabilizing inhibitory nodes and diverting ligase activity away from autophagy initiation sites, consistent with a role in negatively regulating macroautophagy and a distribution between the cytosol and nucleus.

Predicted Gene Ontology terms

1. 01

   I begin with the InterPro architecture: a single, expansive family signature IPR033571 (NEDD4-binding protein 3 family) spanning residues 9–544.

   A solitary family domain that covers essentially the full length of the polypeptide indicates a dedicated, non-enzymatic scaffold/adaptor rather than a modular enzyme. Members of this family are defined by selective affinity for NEDD4-class WW-domain E3 ubiquitin ligases and their signaling assemblies. The absence of catalytic subdomains and the breadth of the family signature causally point to a protein whose primary chemistry is multivalent protein-protein interaction, aligning with GO:0005515 protein binding as the molecular function.

2. 02

   From this scaffold identity, I infer how the protein shapes cellular pathways.

   NEDD4-class ligases and their adaptors frequently tune membrane trafficking and autophagy initiation by controlling ubiquitination of autophagy regulators and cargo receptors. A scaffold that binds NEDD4 machinery can sequester or spatially modulate these ligases away from autophagosome biogenesis hubs, thereby dampening autophagic flux. This causal role—controlling ligase positioning and substrate access—maps directly to GO:0016242 negative regulation of macroautophagy.

3. 03

   Cellular placement follows from the same architecture and inferred role.

   A soluble adaptor that assembles ubiquitin-ligase and signaling complexes typically resides in the cytosol, where it can intercept trafficking and autophagy pathways; this supports GO:0005829 cytosol. The documented presence in the nucleus is consistent with shuttling scaffolds that coordinate transcriptional programs and cell-cycle checkpoints that intersect with autophagy and membrane remodeling, supporting GO:0005634 nucleus. Together, a cytosol–nucleus distribution enables the protein to couple cytoplasmic ubiquitin signaling with nuclear regulatory circuits.

4. 04

   Mechanistically, I hypothesize that the protein forms a bipartite platform: one surface engages NEDD4-family ligases and their WW-domain partners, while other regions recruit membrane- or chromatin-associated factors.

   By redistributing NEDD4 assemblies away from autophagy initiation sites and toward nuclear or cytosolic pools, the scaffold reduces ubiquitin-dependent turnover of autophagy inhibitors and stabilizes inhibitory nodes, thereby suppressing autophagosome formation. Likely interaction partners include NEDD4 and NEDD4L ligases, WW-domain adaptors that route ubiquitin signaling, and autophagy regulators that are sensitive to ubiquitin-mediated control. This adaptor-centric mechanism explains its soluble localization and its ability to negatively regulate macroautophagy through spatial control of ubiquitin signaling.