| First Author | Posey KL | Year | 2019 |
| Journal | Am J Pathol | Volume | 189 |
| Issue | 1 | Pages | 132-146 |
| PubMed ID | 30553437 | Mgi Jnum | J:270933 |
| Mgi Id | MGI:6276515 | Doi | 10.1016/j.ajpath.2018.09.008 |
| Citation | Posey KL, et al. (2019) Novel mTORC1 Mechanism Suggests Therapeutic Targets for COMPopathies. Am J Pathol 189(1):132-146 |
| abstractText | Cartilage oligomeric matrix protein (COMP) is a large, multifunctional extracellular protein that, when mutated, is retained in the rough endoplasmic reticulum (ER). This retention elicits ER stress, inflammation, and oxidative stress, resulting in dysfunction and death of growth plate chondrocytes. While identifying the cellular pathologic mechanisms underlying the murine mutant (MT)-COMP model of pseudoachondroplasia, increased midline-1 (MID1) expression and mammalian target of rapamycin complex 1 (mTORC1) signaling was found. This novel role for MID1/mTORC1 signaling was investigated since treatments shown to repress the pathology also reduced Mid1/mTORC1. Although ER stress-inducing drugs or tumor necrosis factor alpha (TNFalpha) in rat chondrosarcoma cells increased Mid1, oxidative stress did not, establishing that ER stress- or TNFalpha-driven inflammation alone is sufficient to elevate MID1 expression. Since MID1 ubiquitinates protein phosphatase 2A (PP2A), a negative regulator of mTORC1, PP2A was evaluated in MT-COMP growth plate chondrocytes. PP2A was decreased, indicating de-repression of mTORC1 signaling. Rapamycin treatment in MT-COMP mice reduced mTORC1 signaling and intracellular retention of COMP, and increased proliferation, but did not change inflammatory markers IL-16 and eosinophil peroxidase. Lastly, mRNA from tuberous sclerosis-1/2-null mice brain tissue exhibiting ER stress had increased Mid1 expression, confirming the relationship between ER stress and MID1/mTORC1 signaling. These findings suggest a mechanistic link between ER stress and MID1/mTORC1 signaling that has implications extending to other conditions involving ER stress. |
