A non-canonical role for the C. elegans dosage compensation complex in growth and metabolic regulation downstream of TOR complex 2

• DOI: 10.1242/dev.094292
• Publication Date: 2013-07-25T14:51:39Z
• Authors: Christopher M. We...; Lianfeng Wu; Denzil Douglas; Alexander A. Soukas
• Keywords: Male; 0301 basic medicine; Blotting, Western; Longevity; Histone-Lysine N-Methyltransferase; Mechanistic Target of Rapamycin Complex 2; Methyltransferases; Protein Serine-Threonine Kinases; Clutch Size; Epigenesis, Genetic; 03 medical and health sciences; Dosage Compensation, Genetic; Multiprotein Complexes; Animals; Body Size; Female; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Carrier Proteins; Energy Metabolism; Adaptor Proteins, Signal Transducing; DNA Primers

The target of rapamycin complex 2 (TORC2) pathway is evolutionarily conserved and regulates cellular energetics, growth and metabolism. Loss of function of the essential TORC2 subunit Rictor (RICT-1) in Caenorhabditis elegans results in slow developmental rate, reduced brood size, small body size, increased fat mass and truncated lifespan. We performed a rict-1 suppressor RNAi screen of genes encoding proteins that possess the phosphorylation sequence of the AGC family kinase SGK, a key downstream effector of TORC2. Only RNAi to dpy-21 suppressed rict-1 slow developmental rate. DPY-21 functions canonically in the ten-protein dosage compensation complex (DCC) to downregulate the expression of X-linked genes only in hermaphroditic worms. However, we find that dpy-21 functions outside of its canonical role, as RNAi to dpy-21 suppresses TORC2 mutant developmental delay in rict-1 males and hermaphrodites. RNAi to dpy-21 normalized brood size and fat storage phenotypes in rict-1 mutants, but failed to restore normal body size and normal lifespan. Further dissection of the DCC via RNAi revealed that other complex members phenocopy the dpy-21 suppression of rict-1, as did RNAi to the DCC effectors set-1 and set-4, which methylate histone 4 on lysine 20 (H4K20). TORC2/rict-1 animals show dysregulation of H4K20 mono- and tri-methyl silencing epigenetic marks, evidence of altered DCC, SET-1 and SET-4 activity. DPY-21 protein physically interacts with the protein kinase SGK-1, suggesting that TORC2 directly regulates the DCC. Together, the data suggest non-canonical, negative regulation of growth and reproduction by DPY-21 via DCC, SET-1 and SET-4 downstream of TORC2 in C. elegans.