NPL4

NPL4 (PF3D7_0507700; annotated PFE0380c) has been identified in the available corpus only by computational prediction, which places it as a component of the conserved Cdc48-NPL4-Ufd1 AAA-ATPase escort complex in P. falciparum, a complex implicated in ubiquitin-dependent extraction of misfolded proteins from the ER membrane for proteasomal degradation (ERAD) (PMID:18545708). Its membership in this complex and its participation in ERAD are inferred by analogy to yeast and human systems and from characterization of flanking ERAD components rather than from any direct assay of NPL4 itself (PMID:22912882). Beyond these predictions, no experimental characterization of NPL4's function, interactions, localization, or substrates has been reported in the available corpus.

1. 2008 Low

   To place an uncharacterized parasite gene into a functional pathway, homology searching asked whether PF3D7_0507700 belongs to a conserved degradation machinery, establishing its predicted identity as a Cdc48-NPL4-Ufd1 escort complex subunit conserved across apicomplexans.

   Evidence BLASTP homology search and OrthoMCL-DB ortholog retrieval identifying orthologs in P. yoelii, C. parvum, C. hominis, and T. gondii

   PMID:18545708

   Open questions at the time

   • Computational prediction only; no experimental validation of NPL4 function or complex membership was performed
   • No demonstration that the parasite protein physically associates with Cdc48/Ufd1
   • Localization of NPL4 not determined
2. 2012 Low

   To situate NPL4 within a specific cellular process, ERAD pathway characterization in P. falciparum modeled it as part of the CDC48-UFD1-NPL4 complex extracting poly-ubiquitylated substrates from the ER for the 26S proteasome, but this placement rested on analogy and on the other ERAD components rather than on NPL4 itself.

   Evidence In vitro ubiquitylation assay and immunofluorescence of other ERAD components (PfUBA1, PfUBC, PfHRD1); NPL4 not directly assayed

   PMID:22912882

   Open questions at the time

   • NPL4 itself was not experimentally interrogated in this study
   • No direct evidence of NPL4 participation in substrate extraction or proteasomal shuttling
   • Interaction of NPL4 with Cdc48 and Ufd1 in the parasite unconfirmed

• Direct experimental characterization of NPL4 — its physical partners, localization, and functional role in ERAD in P. falciparum — remains to be established.
• No direct biochemical demonstration of Cdc48-NPL4-Ufd1 complex assembly in the parasite
• No genetic or knockdown evidence for NPL4 function in ERAD
• No experimentally determined subcellular localization for NPL4