Discovery of nuclear p62-PI4,5P 2 colocalization suggests a new regulatory layer in cancer proteostasis

Aggrephagy, the selective autophagic clearance of protein aggregates, is essential for maintaining cellular homeostasis, particularly in cancer cells undergoing metabolic or proteotoxic stress. This process is mediated by the cargo receptor p62 (sequestosome-1, SQSTM1), which canonically recognizes ubiquitinated protein aggregates in the cytoplasm and delivers them to autophagosomes for lysosomal degradation. Intriguingly, p62 is also detected within nuclear condensates, a phenomenon that remains poorly understood given that autophagy has traditionally been regarded as a strictly cytoplasmic pathway. Within the Phox and Bem1 (PB1) domain of p62, we identified a putative polybasic motif (PBM) capable of binding nuclear phosphoinositides, as well as a ZZ domain previously implicated in DNA binding. Because nuclear phosphoinositides and the kinases that generate them, such as phosphatidylinositol 4-phosphate 5-kinase type 1 alpha (PIP5K1A), regulate transcription, DNA repair, and other spatially organized nuclear processes, we hypothesized that p62 may engage lipid-defined microenvironments within the nucleus. To test this hypothesis, we examined the nuclear interplay of p62 with the signaling lipid phosphatidylinositol 4,5-bisphosphate (PI4,5P 2 ) generated by PIP5K1A. We identified a previously unrecognized nuclear colocalization of p62 and PI4,5P 2 in breast cancer cell lines, a pattern not observed in pancreatic ductal adenocarcinoma (PDAC) models, suggesting that nuclear lipid-p62 regulation is highly cell-type specific. Nutrient deprivation reduced both p62 puncta and total p62 protein abundance, indicating that p62 levels are tightly coupled to metabolic status. Notably, genetic loss of PIP5K1A decreased total p62 levels independent of nutrient conditions, revealing that phosphoinositide signaling and metabolic cues converge to control p62 expression. Together, these findings uncover a novel nuclear interaction between p62 and PI4,5P 2 and point to a regulatory axis involving PIP5K1A that may influence nuclear condensate formation and p62-dependent stress responses. Ongoing studies using proximity ligation assays, lysosomal activity measurements, and pharmacologic perturbation aim to define the functional significance of this pathway, which may represent an unrecognized therapeutic vulnerability in cancers dependent on p62-mediated proteostasis.