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Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes
Journal article   Open access   Peer reviewed

Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes

Rebecca S Hesterberg, Matthew S Beatty, Ying Han, Mario R Fernandez, Afua A Akuffo, William E Goodheart, Chunying Yang, Shiun Chang, Christelle M Colin, Aileen Y Alontaga, …
Blood, Vol.136(7), pp.857-870
08/13/2020
DOI: 10.1182/blood.2019003257
PMCID: PMC7426646
PMID: 32403132
url
https://doi.org/10.1182/blood.2019003257View
Published (Version of record) Open Access

Abstract

Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only molecular target for this drug class, where drug-induced, ubiquitin-dependent degradation of known "neosubstrates," such as IKAROS, AIOLOS, and CK1α, accounts for their biological activity. Far less clear is whether these CRBN E3 ligase-modulating compounds disrupt the endogenous functions of CRBN. We report that CRBN functions in a feedback loop that harnesses antigen-specific CD8+ T-cell effector responses. Specifically, Crbn deficiency in murine CD8+ T cells augments their central metabolism manifested as elevated bioenergetics, with supraphysiological levels of polyamines, secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Treatment with CRBN-modulating compounds similarly augments central metabolism of human CD8+ T cells. Notably, the metabolic control of CD8+ T cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn-deficient T cells have augmented antigen-specific cytolytic activity vs melanoma tumor cells, ex vivo and in vivo, and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of CD8+ T cells, and this phenotype can be exploited by treatment with drugs.
 Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - physiology Animals CD8-Positive T-Lymphocytes - metabolism CD8-Positive T-Lymphocytes - physiology Cells, Cultured Energy Metabolism - genetics Immunomodulation - genetics Lymphocyte Activation - genetics Melanoma, Experimental - pathology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic Proto-Oncogene Proteins c-myc - genetics

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