{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNPLOC4 functions as a critical adaptor within the p97 (VCP) ATPase machinery, mediating the recognition and processing of polyubiquitinated substrates for proteasomal degradation. In several in vitro reconstitution studies, NPLOC4, in partnership with UFD1L, has been shown to be essential for the unfolding activity of p97 on ubiquitinated substrates – a process that underpins diverse cellular pathways such as endoplasmic reticulum–associated degradation (ERAD) and the regulation of NF‐κB signaling by targeting inhibitory proteins. This adaptor role is further highlighted by studies demonstrating that mutations impacting p97’s interaction with NPLOC4 can accelerate substrate processing, suggesting that heightened or dysregulated NPLOC4–p97 activity contributes to disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond substrate unfolding, NPLOC4 is integral to several additional cellular functions. Detailed cryo‐electron microscopy and structural analyses have revealed that NPLOC4’s zinc finger and other conserved domains dictate its dynamic engagement with p97 and its regulation by additional cofactors such as UBX proteins, thereby fine‐tuning substrate recognition and processing thresholds. Moreover, NPLOC4-containing p97 complexes participate in the removal or processing of key regulators during mitosis and the DNA damage response—including the extraction of Aurora B kinase from chromosomes and the regulated degradation of checkpoint regulators—underscoring its pivotal role in maintaining genomic stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIntriguingly, context‐dependent studies also reveal that NPLOC4’s involvement may vary; in certain retrotranslocation processes—such as those hijacked by pathogens like human cytomegalovirus or cholera toxin—NPLOC4 (and its partner UFD1L) can be dispensable or may even function as a regulatory brake to delay substrate extraction. In parallel, NPLOC4 is emerging as a clinically relevant biomarker and therapeutic target. Elevated NPLOC4 expression in cancers such as clear cell renal cell carcinoma and lung squamous cell carcinoma correlates with poor patient prognosis, and small molecules like disulfiram (especially when complexed with copper) have been found to target NPLOC4, thereby sensitizing tumor cells to apoptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "16"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ju-Mei Li, Hongyu Wu, Wenzheng Zhang, et al. 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