Crystallin-αB regulates skeletal muscle homeostasis via modulation of argonaute2 activity.
The core functional machinery of the RNAi pathway is the RNA-induced silencing complex (RISC), wherein Argonaute2 (Ago2) is essential for siRNA-directed endonuclease activity and RNAi/microRNA-mediated gene silencing. Crystallin-αB (CryAB) is a small heat shock protein involved in preventing protein aggregation. We demonstrate that CryAB interacts with the N and C termini of Ago2, not the catalytic site defined by the convergence of the PAZ, MID, and PIWI domains. We further demonstrate significantly reduced Ago2 activity in the absence of CryAB, highlighting a novel role of CryAB in the mammalian RNAi/microRNA pathway. In skeletal muscle of CryAB null mice, we observe a shift in the hypertrophy-atrophy signaling axis toward atrophy under basal conditions. Moreover, loss of CryAB altered the capability of satellite cells to regenerate skeletal muscle. These studies establish that CryAB is necessary for normal Ago2/RISC activity and cellular homeostasis in skeletal muscle.
From the Department of Cardiology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 and rneppl@enders.tch.harvard.edu.
Ronald L
RL
Neppl
From the Department of Cardiology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 and.
Masaharu
M
Kataoka
From the Department of Cardiology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138 dwang@enders.tch.harvard.edu.
Da-Zhi
DZ
Wang
D000818:Animals; D060565:Argonaute Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D020134:Catalytic Domain; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D034743:RNA-Induced Silencing Complex / Q000378:metabolism; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000502:physiology; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism*
C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; C525420:Cryab protein, mouse; D035683:MicroRNAs; D034743:RNA-Induced Silencing Complex; D038203:alpha-Crystallin B Chain
Argonaute2; Crystallin; MicroRNA (miRNA); RNA Interference (RNAi); Skeletal Muscle; Small Heat Shock Protein (sHsp)