Cellular Differences in Protein Synthesis Regulate Tissue Homeostasis

Buszczak, Michael; Signer, Robert A.J.; Morrison, Sean J.

doi:10.1016/j.cell.2014.09.016

Cited by 183 publications

(167 citation statements)

References 112 publications

(171 reference statements)

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“…As mTORC1 activities are also controlled by growth factor signaling, cellular energy, and stress levels, the alteration of the recycling pathway reported here likely has much wider significance not limited to nutrient conditions. Indeed, the level of mTORC1 activity varies greatly among cell types in vivo, particularly activities involved in tissue homeostasis such as self-renewal and differentiation of stem cell (24). The results reported here, therefore, represent a major development in our understanding of the recycling pathway.…”

Section: Discussionmentioning

confidence: 91%

mTOR complex 1 activity is required to maintain the canonical endocytic recycling pathway against lysosomal delivery

Dauner

Eid

Raghupathy

et al. 2017

Journal of Biological Chemistry

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Edited by Thomas SöllnerThe plasma membrane of mammalian cells undergoes constitutive endocytosis, endocytic sorting, and recycling, which delivers nutrients to the lysosomes. The receptors, along with membrane lipids, are normally returned to the plasma membrane to sustain this action. It is not known, however, whether this process is influenced by metabolic conditions. Here we report that endocytic recycling requires active mechanistic target of rapamycin (aka mammalian target of rapamycin) (mTORC1), a master metabolic sensor. Upon mTORC1 inactivation, either by starvation or by inhibitor, recycling receptors and plasma membrane lipids, such as transferrin receptors and sphingomyelin, are delivered to the lysosomes. This lysosomal targeting is independent of canonical autophagy: both WT and Atg5 ؊/؊ mouse embryonic fibroblasts responded similarly. Furthermore, we identify hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), an endosomal sorting complexes required for transport (ESCORT-0) component, as a downstream target of mTORC1. Hrs requires mTORC1 activity to maintain its protein expression level. Silencing Hrs without decreasing mTORC1 activity is sufficient to target transferrin and sphingomyelin to the lysosomes. It is thus evident that the canonical recycling pathway is under the regulation of mTORC1 and likely most predominant in proliferating cells where mTORC1 is highly active.

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Section: Discussionmentioning

confidence: 91%

mTOR complex 1 activity is required to maintain the canonical endocytic recycling pathway against lysosomal delivery

Dauner

Eid

Raghupathy

et al. 2017

Journal of Biological Chemistry

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“…Indeed, the massive pGE observed in mTEC hi must represent a challenge for proteostasis in these cells. Assuming that promiscuously expressed genes are translated, mTEC hi must have to deal with high intracellular protein levels that would normally trigger proteotoxic stress response and proliferative exhaustion (61). There are only two ways to deal with this problem: by decreasing translation or increasing protein degradation.…”

Section: Discussionmentioning

confidence: 99%

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

St-Pierre

Trofimov

Brochu

et al. 2015

The Journal of Immunology

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Establishment of self-tolerance in the thymus depends on promiscuous expression of tissue-restricted Ags (TRA) by thymic epithelial cells (TEC). This promiscuous gene expression (pGE) is regulated in part by the autoimmune regulator (AIRE). To evaluate the commonalities and discrepancies between AIRE-dependent and -independent pGE, we analyzed the transcriptome of the three main TEC subsets in wild-type and Aire knockout mice. We found that the impact of AIRE-dependent pGE is not limited to generation of TRA. AIRE decreases, via non–cell autonomous mechanisms, the expression of genes coding for positive regulators of cell proliferation, and it thereby reduces the number of cortical TEC. In mature medullary TEC, AIRE-driven pGE upregulates non-TRA coding genes that enhance cell–cell interactions (e.g., claudins, integrins, and selectins) and are probably of prime relevance to tolerance induction. We also found that AIRE-dependent and -independent TRA present several distinctive features. In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous and show greater splicing complexity. Furthermore, we report that AIRE-dependent versus -independent TRA project nonredundant representations of peripheral tissues in the thymus.

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“…Indeed, mutations in genes encoding ribosome components often result in cell type-specific phenotypes (Buszczak et al, 2014). Similarly, the occurrence of m 5 C at distinct sites in rRNAs may directly influence ribosomal activity to favour cell type-specific translational programmes.…”

Section: Mechanism Of Action Of Cytosine-5 Methylationmentioning

confidence: 99%

Post-transcriptional modifications in development and stem cells

Frye

Blanco

2016

Development

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Cells adapt to their environment by linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. Among these, mechanisms that couple environmental cues to the regulation of protein translation are not well understood. Chemical modifications of RNA allow rapid cellular responses to external stimuli by modulating a wide range of fundamental biochemical properties and processes, including the stability, splicing and translation of messenger RNA. In this Review, we focus on the occurrence of N 6 -methyladenosine (m 6 A), 5-methylcytosine (m 5 C) and pseudouridine (Ψ) in RNA, and describe how these RNA modifications are implicated in regulating pluripotency, stem cell self-renewal and fate specification. Both post-transcriptional modifications and the enzymes that catalyse them modulate stem cell differentiation pathways and are essential for normal development.

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Cellular Differences in Protein Synthesis Regulate Tissue Homeostasis

Cited by 183 publications

References 112 publications

mTOR complex 1 activity is required to maintain the canonical endocytic recycling pathway against lysosomal delivery

mTOR complex 1 activity is required to maintain the canonical endocytic recycling pathway against lysosomal delivery

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

Post-transcriptional modifications in development and stem cells

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