FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation

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High mTORC1 signaling is maintained,while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state

This study investigated age-associated changes to protein synthesis and degradation pathways in the quadriceps muscles of male C57BL/6J mice at 5 ages, between 4 and 24 months (m). Sarcopenia was evident by 18 m and was accompanied by hyper-phosphorylation of S6K1, indicating increased mTORC1 signaling. Proteasomal and autophagosomal degradation pathways were also impacted by aging. In the 1% NP40 insoluble protein fraction, the abundance of MuRF1 increased at 24 m, while p62 increased at 15 m, and remained elevated at older ages. In addition, we investigated how protein synthesis and degradation pathways are modulated by fasting in young (4 m) and old (24 m) muscles, and showed that old mice respond to fasting less robustly compared with young. Overnight fasting for 16 h caused de-phosphorylation of AKT and molecules downstream of mTORC1 (S6K1, rpS6 and 4E-BP1) in young, but not old muscles. A longer time of fasting (24 h) was required to reduce phosphorylation of these molecules in old mice. Induction of MuRF1 and Fbxo32 mRNA was also more robust in young compared with old muscles following fasting for 16 h. In addition, a 16 h fast reduced ULK1 phosphorylation at the mTORC1 specific site Ser757 only in young muscles. The striking accumulation of insoluble p62 protein in muscles of all old male mice (fed or fasted), suggests age-related dysregulation of autophagy and protein aggregation. These data provide an insight into the mechanisms of metabolic responses that affect protein homeostasis in old skeletal muscles, with applications to design of clinical interventions that target sarcopenia.     

NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C

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Multiple facets of TRPML1 in autophagy

Autophagy is an evolutionarily conserved pathway that is required for cellular homeostasis, growth and survival. In a recent study, Scotto-Rosato et al. demonstrate that TRPML1-mediated calcium release promotes autophagosome biogenesis by activating the CaMKKβ/VPS34 pathway, providing a new insight into the pathophysiological role of TRPML1 in human diseases.     

Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation

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Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition

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To B,or not to B: Is calcium the answer?

B lymphocytes are an important component of the adaptive and innate immune system because of their ability to secrete antibodies and to present antigens to T cells, which is critical for immune responses to many pathogens. Abnormal B cell function is the cause of diseases including autoimmune, paraneoplastic, and immunodeficiency disorders. The development, survival, and function of B cells depend on signaling through the B cell receptor (BCR) and costimulatory receptors. One of the signaling pathways induced by antigen binding to the BCR is store-operated Ca²⁺ entry (SOCE), which depends on the Ca²⁺ channel ORAI1 and its activators stromal interaction molecule (STIM) 1 and 2. A recent study by Berry et al. [1] reports that B cells lacking STIM1 and STIM2 fail to survive and proliferate because abolished SOCE results in impaired expression of two key anti-apoptotic genes and blunted activation of mTORC1 and c-Myc signaling. The associated Ca²⁺ regulated checkpoints of B cell survival and proliferation can be bypassed, at least partially, by costimulation through CD40 or TLR9. This study provides important new insights on how SOCE controls B cell function.