harbors C-terminal sequence variants (G1 and G2), which account for much of the increased risk for kidney disease in sub-Saharan African ancestry populations. Expression of the risk variants has also been shown to cause injury to podocytes and other cell types, but the underlying mechanisms are not understood. We used and to help clarify these mechanisms. Ubiquitous expression of the human APOL1 G1 and G2 disease risk alleles caused near-complete lethality in , with no effect of the G0 nonrisk allele, corresponding to the pattern of human disease risk. We also observed a congruent pattern of cellular damage with tissue-specific expression of APOL1. In particular, expression of APOL1 risk variants in nephrocytes caused cell-autonomous accumulation of the endocytic tracer atrial natriuretic factor-red fluorescent protein at early stages and nephrocyte loss at later stages. We also observed differential toxicity of the risk variants compared with the nonrisk variants in, including impairment of vacuole acidification. Yeast strains defective in endosomal trafficking or organelle acidification but not those defective in autophagy displayed augmented APOL1 toxicity with all isoforms. This pattern of differential injury by the APOL1 risk alleles compared with the nonrisk alleles across evolutionarily divergent species is consistent with an impairment of conserved core intracellular endosomal trafficking processes. This finding should facilitate the identification of cell injury pathways and corresponding therapeutic targets of interest in these amenable experimental platforms.

The RTK/Ras/Raf cascade is overactive in cancers. Its targets are the MAP kinases Erks, but Erks are not mutated in cancers. An active Erk, Erk1(R84S), is an oncoprotein. Further, Erk1(R84S) and Erk2(R65S) autophosphorylate the TEY motif and Thr-207/Thr-188. Erk2(R65S) autophosphorylates Thr-188 when dually mutated in the TEY.

JDP2, is a basic leucine zipper (bZIP) protein displaying a high degree of homology with the stress inducible transcription factor, ATF3. Both proteins bind to cAMP and TPA response elements and repress transcription by multiple mechanisms. Histone deacetylases (HDACs) play a key role in gene inactivation by deacetylating lysine residues on histones. Here we describe the association of JDP2 and ATF3 with HDACs 1, 2–6 and 10. Association of HDAC3 and HDAC6 with JDP2 and ATF3 occurs via direct protein-protein interactions. The N-terminal bZIP motif of JDP2 and ATF3 basic domain are necessary and sufficient for the interaction with HDACs in a manner that is independent of coiled-coil dimerization. Class I HDACs associate with the bZIP repressors via the DAC conserved domain whereas the Class IIb HDAC6 associates through its C-terminal unique binder of ubiquitin Zn finger domain. Both JDP2 and ATF3 are known to bind and repress the ATF3 promoter. MEF cells treated with histone deacetylase inhibitor, trichostatin A (TSA) display enhanced ATF3 transcription. ATF3 enhanced transcription is significantly reduced in MEF cells lacking both ATF3 and JDP2. Collectively, we propose that the recruitment of multiple HDAC members to JDP2 and ATF3 is part of their transcription repression mechanism.

Background: WDR62 is a JNK scaffold protein. Results:We identified at the WDR62 C terminus a loop-helix domain that is responsible for its homodimerization and association with another JNK scaffold protein, MAPKBP1. WDR62 dimerization is required for JNK and MKK7␤1 recruitment. Conclusion: WDR62 dimerization is required for its scaffolding function. Significance: Scaffold protein association offers another layer of complexity for the fine tuning of signaling pathways.