CDC48

In Toxoplasma gondii, the CDC48 family comprises two distinct AAA-ATPases that operate in separate cellular compartments. CDC48AP localizes to the apicoplast and is required for translocation of nucleus-encoded apicoplast proteins across the periplastid membrane, functioning with the plastid ubiquitin-like protein PUBL as part of an apicoplast-specific ERAD-like import machinery (PMID:28655825). The second family member, TgNoAP1, localizes to the nucleolus during G1/S phase and is required for 28S pre-rRNA processing, interacting with components of the snoRNP and R2TP complexes; its loss via a temperature-sensitive allele causes conditional protein instability and G1-phase cell cycle arrest (PMID:23964771). Beyond these two studies, no further mechanistic detail on CDC48 family function has been characterized in the available corpus.

1. 2013 High

   Established that a nucleolar CDC48-family AAA-ATPase couples ribosome biogenesis to cell cycle progression in Toxoplasma, answering whether this protein family has a role beyond membrane-associated functions.

   Evidence Temperature-sensitive mutant mapping by genetic complementation, knock-in point mutation, microscopy, co-immunoprecipitation with snoRNP/R2TP factors, and rRNA processing assay in T. gondii

   PMID:23964771

   Open questions at the time

   • The direct enzymatic role of TgNoAP1 ATPase activity in pre-rRNA processing is not resolved
   • The molecular mechanism linking rRNA processing defect to G1 arrest is not defined
2. 2017 High

   Established that a second CDC48-family AAA-ATPase drives apicoplast protein import, answering how nucleus-encoded proteins are translocated across the periplastid membrane via an ERAD-like route.

   Evidence Conditional null mutants, genetic complementation, functional import assays, and PUBL residue mutagenesis in T. gondii

   PMID:28655825

   Open questions at the time

   • The full set of translocated substrates is not defined
   • The structural organization of the CDC48AP/PUBL ERAD-like complex is not resolved
   • How CDC48AP recognizes ubiquitin-like PUBL-tagged cargo is not established

• Whether and how the two CDC48-family ATPases are functionally or evolutionarily related, and their respective substrate spectra, remain unresolved.
• No shared cofactor or regulatory logic linking the two paralogs is characterized
• No structural model exists for either ATPase in Toxoplasma