SDF2 and SDF2L1 are essential co-factors of DNAJB11 for Polycystin-1 processing.

Mutations in the co-chaperone DNAJB11 have been shown to cause polycystic kidney disease. The molecular mechanism underlying DNAJB11-related kidney disease involves impaired processing of Polycystin-1 (PC1), the protein most commonly mutated in autosomal dominant polycystic kidney disease (ADPKD). Chaperones are known to form multiprotein complexes to facilitate folding and processing of client proteins. Yet, it is unknown whether DNAJB11 forms complexes with other proteins that are required for PC1 processing. In this study, we perform an unbiased interaction proteomics screen for DNAJB11-interacting proteins. We identify two highly homologous proteins, SDF2 and SDF2L1, as strong interaction partners of DNAJB11. Using newly established knockout cell lines, we demonstrate a reciprocal interdependence of DNAJB11 and SDF2/SDF2L1 protein abundance. Furthermore, we show that concomitant loss of SDF2 and SDF2L1 impairs PC1 processing, mimicking the biochemical phenotype caused by loss of DNAJB11. Using a combination of knockout cell lines and reexpression of the respective members of the DNAJB11 protein complex, we show that SDF2 or SDF2L1 are elementary subunits of the DNAJB11 complex required for normal PC1 processing.