Mevalonate metabolism-dependent protein geranylgeranylation regulates thymocyte egress

Xingrong Du, Hu Zeng, Shaofeng Liu, Cliff Guy, Yogesh Dhungana, Geoffrey Neale, Martin O. Bergo, Hongbo Chi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalThe Journal of experimental medicine
Volume217
Issue number2
DOIs
StatePublished - Feb 3 2020

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Protein Prenylation
Mevalonic Acid
Thymocytes
Homeostasis
T-Lymphocytes
Farnesyltranstransferase
Prenylation
Lymphopenia
Emigration and Immigration
Adaptive Immunity
Post Translational Protein Processing
G-Protein-Coupled Receptors
Chemokines

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mevalonate metabolism-dependent protein geranylgeranylation regulates thymocyte egress. / Du, Xingrong; Zeng, Hu; Liu, Shaofeng; Guy, Cliff; Dhungana, Yogesh; Neale, Geoffrey; Bergo, Martin O.; Chi, Hongbo.

In: The Journal of experimental medicine, Vol. 217, No. 2, 03.02.2020.

Research output: Contribution to journalArticle

Du, Xingrong ; Zeng, Hu ; Liu, Shaofeng ; Guy, Cliff ; Dhungana, Yogesh ; Neale, Geoffrey ; Bergo, Martin O. ; Chi, Hongbo. / Mevalonate metabolism-dependent protein geranylgeranylation regulates thymocyte egress. In: The Journal of experimental medicine. 2020 ; Vol. 217, No. 2.
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