4.8 Article

Pharmacological inhibition of lysosomes activates the MTORC1 signaling pathway in chondrocytes in an autophagy-independent manner

Journal

AUTOPHAGY
Volume 11, Issue 9, Pages 1594-1607

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2015.1068489

Keywords

autophagy; bafilomycin; bone; chondrocyte; lysosome; MTOR; MTORC1

Categories

Funding

  1. Swedish Research Council [521-2012-1543]
  2. HKH Kronprinsessan Lovisas forening for Barnasjukvard
  3. Jeanssons stiftelser
  4. Ake-Wiberg Stiftelse
  5. Karolinska Institutet
  6. Sallskapet Barnavard
  7. Tore Nilsons Stiftelse for medical research (SEB stiftelser)

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Mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) is a protein-signaling complex at the fulcrum of anabolic and catabolic processes, which acts depending on wide-ranging environmental cues. It is generally accepted that lysosomes facilitate MTORC1 activation by generating an internal pool of amino acids. Amino acids activate MTORC1 by stimulating its translocation to the lysosomal membrane where it forms a super-complex involving the lysosomal-membrane-bound vacuolar-type H+-ATPase (v-ATPase) proton pump. This translocation and MTORC1 activation require functional lysosomes. Here we found that, in contrast to this well-accepted concept, in epiphyseal chondrocytes inhibition of lysosomal activity by v-ATPase inhibitors bafilomycin A(1) or concanamycin A potently activated MTORC1 signaling. The activity of MTORC1 was visualized by phosphorylated forms of RPS6 (ribosomal protein S6) and EIF4EBP1, 2 well-known downstream targets of MTORC1. Maximal RPS6 phosphorylation was observed at 48-h treatment and reached as high as a 12-fold increase (p < 0.018). This activation of MTORC1 was further confirmed in bone organ culture and promoted potent stimulation of longitudinal growth (p < 0.001). Importantly, the same effect was observed in ATG5 (autophagy-related 5)-deficient bones suggesting a macroautophagy-independent mechanism of MTORC1 inhibition by lysosomes. Thus, our data show that in epiphyseal chondrocytes lysosomes inhibit MTORC1 in a macroautophagy-independent manner and this inhibition likely depends on v-ATPase activity.

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