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

Development. 2013 Sep;140(17):3601-12. doi: 10.1242/dev.094292. Epub 2013 Jul 24.

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.

Keywords: Aging; C. elegans; Dosage compensation complex (DCC); Epigenetics; Growth; Metabolism; Rictor; TOR complex 2 (TORC2); Target of rapamycin (TOR); dpy-21.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Blotting, Western
  • Body Size / genetics
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Clutch Size / genetics
  • DNA Primers / genetics
  • Dosage Compensation, Genetic / genetics*
  • Energy Metabolism / genetics
  • Energy Metabolism / physiology*
  • Epigenesis, Genetic / physiology
  • Female
  • Histone-Lysine N-Methyltransferase / metabolism
  • Longevity / genetics
  • Male
  • Mechanistic Target of Rapamycin Complex 2
  • Methyltransferases / metabolism
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Rapamycin-Insensitive Companion of mTOR Protein
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • DNA Primers
  • DPY-21 protein, C elegans
  • Multiprotein Complexes
  • Rapamycin-Insensitive Companion of mTOR Protein
  • rict-1 protein, C elegans
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • SET-4 protein, C elegans
  • Set-1 protein, C elegans
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2
  • Protein-Serine-Threonine Kinases
  • Sgk-1 protein, C elegans