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Heterozygous mutations in the human VCP (p97) gene cause autosomal-dominant IBMPFD (inclusion body myopathy with early onset Paget’s disease of bone and frontotemporal dementia), ALS14 (amyotrophic lateral sclerosis with or without frontotemporal dementia) and HSP (hereditary spastic paraplegia). Most prevalent is the R155C point mutation. We studied the function of p97 in the social amoeba  Dictyostelium discoideum  and have generated strains that ectopically express wild-type (p97) or mutant p97 (p97 R155C ) fused to RFP in AX2 wild-type and autophagy 9 knock-out (ATG9 KO ) cells. Native gel electrophoresis showed that both p97 and p97 R155C  assemble into hexamers. Co-immunoprecipitation studies revealed that endogenous p97 and p97 R155C -RFP form heteromers. The mutant strains displayed changes in cell growth, phototaxis, development, proteasomal activity, ubiquitinylated proteins, and ATG8(LC3) indicating mis-regulation of multiple essential cellular processes. Additionally, immunofluorescence analysis revealed an increase of protein aggregates in ATG9 KO /p97 R155C -RFP and ATG9 KO  cells. They were positive for ubiquitin in both strains, however, solely immunoreactive for p97 in the ATG9 KO  mutant. A major finding is that the expression of p97 R155C -RFP in the ATG9 KO  strain partially or fully rescued the pleiotropic phenotype. We also observed dose-dependent effects of p97 on several cellular processes. Based on findings in the single versus the double mutants we propose a novel mode of p97 interaction with the core autophagy protein ATG9 which is based on mutual inhibition.

Heteromeric p97/p97R155C Complexes Induce Dominant Negative Changes in Wild-Type and Autophagy 9-Deficient Dictyostelium strains