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Fine-tuning of thymocyte development by ubiquitination-mediated stability control of the ESCRT protein CHMP5

Cellular & Molecular Immunology volume 14, pages 957–959 (2017)Cite this article

Tlymphocytes are generated from hematopoietic stem cells in bone marrow, mature in the thymus and migrate to peripheral lymphoid tissues. The thymus is composed of the cortex and medulla, and there are many immature thymocytes in the cortex and more mature thymocytes are present in the medulla. Developing thymocytes expressing T-cell receptor (TCR) αβ chains generated by TCR gene rearrangement selectively differentiate only when they are determined to be useful cells by judgement of the strength of interaction between their TCR and peptide antigens presented on major histocompatibility complex (MHC) molecules of cortical thymic epithelial cells (cTECs). Cells unable to recognize peptide-MHC ligands cannot receive survival signals, and only cells that can recognize peptide-MHC ligands with an appropriate affinity proliferate and differentiate into mature T cells. This checkpoint mechanism is called positive selection. On the other hand, cell death is induced in cells that show strong responses to peptide-MHC ligands, a mechanism that is called negative selection. Although the mechanism that produces different responses depending on the affinity between TCR and peptide-MHC ligands has not been unclear, the mitogen-activated protein kinase (MAPK) pathway, and strength and localization of downstream signals in TCR stimulation are likely involved in regulation of the selection process of T cells.1 For example, p38, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase 5 (ERK5) are important MAPK signals for negative selection but are not required for positive selection. On the other hand, phosphorylation of ERK1/2 is important for positive selection but not for negative selection. It is also known that localization of phosphorylated ERK differs between positive selection and negative selection. Stimuli of negative selection induce phosphorylated ERK closer to the plasma membrane than stimuli of positive selection do. As a new mechanism not dependent on the MAPK pathway, Adoro et al.2 recently reported that an adequate input of TCR promotes the survival of positively selected thymocytes via the stabilization of one of the pro-survival factors, B-cell lymphoma 2 (Bcl-2).

Endosomal sorting complex required for transport (ESCRT) is a system necessary for separating membranes, forming and transporting vesicles, and forming multivesicular bodies (MVBs). Multiple ESCRT proteins are involved in this system: early-acting ESCRT proteins are first recruited to the site of membrane detachment and they recruit late-acting ESCRT proteins. These late-acting ESCRT proteins are also known as the charged MVB protein (CHMP) family and are involved in membrane deformity and isolation in cooperation with VPS4. There are seven CHMP genes in budding yeasts and eleven CHMP genes in humans, and they are classified into subgroups of CHMP1 to CHMP7. The relationship between ESCRT proteins and T-cell differentiation has been unclear, but Adoro et al. showed that CHMP5 is essential for T-cell differentiation. However, CHMP5 likely contributes to T-cell differentiation via functions other than that in the ESCRT pathway, because CHMP5 is dispensable in the ESCRT pathway in developing thymocytes.

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Acknowledgements

This work was supported in part by KAKENHI (15H04690, 17H05784 and 17K19506 to SH; 16H06221 and 17H05989 to MW), Takeda Science Foundation (to SH), Japan Foundation for Applied Enzymology (to SH), Grant-in-Aid from Tokyo Biochemical Research Foundation (to SH) and Nakatani Foundation for advancement of measuring technologies in biomedical engineering (to MW).

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  1. Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638, Hokkaido, Japan

    Masashi Watanabe & Shigetsugu Hatakeyama

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  1. Masashi Watanabe
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Correspondence to Shigetsugu Hatakeyama.

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Watanabe, M., Hatakeyama, S. Fine-tuning of thymocyte development by ubiquitination-mediated stability control of the ESCRT protein CHMP5. Cell Mol Immunol 14, 957–959 (2017). https://doi.org/10.1038/cmi.2017.91

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