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J Exp Med. 2020 Feb 3;217(2). pii: e20190969. doi: 10.1084/jem.20190969.

Mevalonate metabolism-dependent protein geranylgeranylation regulates thymocyte egress.

Author information

1
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN.
2
Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN.
3
Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
4
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

Abstract

Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Despite the roles of G protein-coupled receptors in thymocyte emigration, the downstream signaling mechanism remains poorly defined. Here, we report the discrete roles for the two branches of mevalonate metabolism-fueled protein prenylation pathway in thymocyte egress and immune homeostasis. The protein geranylgeranyltransferase Pggt1b is up-regulated in single-positive thymocytes, and loss of Pggt1b leads to marked defects in thymocyte egress and T cell lymphopenia in peripheral lymphoid organs in vivo. Mechanistically, Pggt1b bridges sphingosine-1-phosphate and chemokine-induced migratory signals with the activation of Cdc42 and Pak signaling and mevalonate-dependent thymocyte trafficking. In contrast, the farnesyltransferase Fntb, which mediates a biochemically similar process of protein farnesylation, is dispensable for thymocyte egress but contributes to peripheral T cell homeostasis. Collectively, our studies establish context-dependent effects of protein prenylation and unique roles of geranylgeranylation in thymic egress and highlight that the interplay between cellular metabolism and posttranslational modification underlies immune homeostasis.

PMID:
31722972
DOI:
10.1084/jem.20190969

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