Research Highlights

 

Nutrients and growth factors activate the mechanistic target of rapamycin complex 1 (mTORC1), a major driver of cellular anabolic processes, growth and proliferation (Efeyan et al., Trends Mol Med 2012). While the cascade triggered by growth factors has been extensively studied in vitro and in vivo, we have just started to understand how nutrients activate mTORC1 (Efeyan et al., Nature 2015). Nutrient levels dictate the nucleotide bound state of the heterodimeric GTPase complex (RagA or RagB with RagC or Rag D). When cellular nutrients are abundant, RagA becomes GTP-loaded, while RagC is loaded with GDP. Upon this configuration, the Rag GTPases interact with mTORC1 and recruit it to the outer lysosomal surface, an essential step in the process of kinase activation. In the last years, we have developed genetic tools (gain-of-function and loss-of-function alleles for the Rag GTPases) to investigate the roles of the nutrient-sensing pathway upstream of mTORC1 in vivo, and taken a field that was mostly characterized by means of cultured cells into physiology, by demonstrating that:

 

1. The nutrient sensing pathway machinery is essential in mammals, with cell and tissue specific differences in the consequences of genetic ablation of the nutrient sensing ability (Efeyan et al., 2014).

2. The inability to sense a drop in cellular nutrients is lethal as soon as trans-placental supply of nutrients in interrupted at birth (Efeyan et al., 2013). Our work showed the essentiality of the regulation of the mTORC1 by nutrients, its critical role in controlling autophagy; and that glucose, in addition to amino acids, controls the activation of the Rag GTPases.

3. Unexpectedly, B lymphocytes are exquisitely sensitive to physiological fluctuation in nutrient signaling, and B lymphocyte immune responses are dismantled upon genetic deregulation in the nutrient signaling pathway (Ersching*, Efeyan* et al., 2017) Moreover, we determined that mTORC1 activity must be dynamically regulated after B lymphocyte activation by antigens and T lymphocytes, to orchestrate the process of cell growth that precedes an intense burst in proliferation.

 

We have recently participated in the identification of recurrent mutations in the nutrient signaling pathway, (in particular, activating mutations in RagC) in B cell lymphomas (Okosun, et al., Nat Genetics 2016). We engineered some of these mutations in mice by means of CRISPR/Cas9 genome targeting and started to interrogate the consequences of activating mutations in the nutrient signaling pathway for normal and pathological B cell functions. B cells participating in an immune response, Germinal Center (GC) B cells, show several features of over-activation when expressing RagC mutations (enlarged GCs, increased plasma cell production, increased proliferation and survival; Figure 1). We are beginning to comprehend the reasons for such a tight control of nutrient-evoked mTORC1 activation on the process of B cell selection, immune response and lymphomagenesis.

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When we experimentally rescue neonatal demise, it is possible to obtain adult mice completely unable to sense a drop in nutrient levels and regulate mTORC1 accordingly (RagAGTP mice). These mice exhibit several metabolic alterations, such as a dramatic reduction in amino acids in circulation, mild hyperglycaemia and glucose intolerance (Figure 2), puzzling observations that we are currently trying to understand.

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you can access all publications in the Publications section