title: A non-canonical role for the C. elegans dosage compensation complex in growth and metabolic regulation downstream of TOR complex 2.
abstract: 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.
authors.affiliation: Center for Human Genetic Research and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Webster
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Wu
authors.forename: Denzil
authors.initials: D
authors.lastname: Douglas
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Soukas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D049628:Body Size / Q000235:genetics; D017173:Caenorhabditis elegans / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D052284:Clutch Size / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004303:Dosage Compensation, Genetic / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D008780:Methyltransferases / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D017931:DNA Primers; C584037:DPY-21 protein, C elegans; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C539011:rict-1 protein, C elegans; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C577070:SET-4 protein, C elegans; C464501:Set-1 protein, C elegans; D000076225:Mechanistic Target of Rapamycin Complex 2; D017346:Protein Serine-Threonine Kinases; C540745:Sgk-1 protein, C elegans; D058570:TOR Serine-Threonine Kinases
keywords: Aging; C. elegans; Dosage compensation complex (DCC); Epigenetics; Growth; Metabolism; Rictor; TOR complex 2 (TORC2); Target of rapamycin (TOR); dpy-21