N-terminal acetylation is one of the most common protein modifications, occurring on approximately 80-90% of mammalian proteins. This modification is generally thought to affect protein localization, stability, and binding affinity. The addition of an acetyl group to the initiation methionine of translating proteins is catalyzed by distinct N-terminal acetyltransferases (NATs). NatA, NatB, and NatC are the three major enzymatic complexes responsible for this co-translational modification in C. elegans. Several studies have shown that NATs play multiple roles in lifespan regulation, meiosis, and metabolism. Here, we report that NatC functions in larval development regulated by the NIPI-3 Tribbles pseudokinase. We previously reported that genetic null mutations of
nipi-3 cause larval development to be arrested in L2/L3 stage and that loss of function of the bZip transcription factor,
cebp-1, and the downstream PMK-1/p38 MAPK pathway fully suppresses the larval lethality of
nipi-3(null)1. We designed a highly efficient scheme to select for suppressor mutations of
nipi-3(null) and isolated many new suppressor alleles. Among them, we have identified a missense mutation within the catalytic domain of
natc-2. We further verified that genetic null mutations of
natc-2 also suppress
nipi-3(null). Additionally, we found that a null mutation of
natc-1, the other catalytic subunit of NatC, also suppresses
nipi-3(null) larval lethality. These results suggest that the activity of the NatC complex is necessary for its interaction with NIPI-3. The substrate of this N-terminal acetylation is unknown. We hypothesize that the co-translational modification occurs to activate one of the genes in the previously described
nipi-3 development pathway1. Additionally, we are characterizing a novel mutant,
ju1541, that does not affect any of the genes previously identified as acting downstream of NIPI-31. Based on whole genome sequencing and SNP mapping of
ju1541 we have identified several candidates and will present the progress to determine the gene affected by this mutation. 1. Kim, K. W., Thakur, N., Piggott, C. A., Omi, S., Polanowska, J., Jin, Y., & Pujol, N. (2016). Coordinated inhibition of C/EBP by Tribbles in multiple tissues is essential for Caenorhabditis elegans development. BMC biology, 14(1), 104.