# Regulation of T cell metabolism by DRAK2

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $183,112

## Abstract

PROJECT SUMMARY
The goal of this new proposal is to identify molecular mechanisms involved in controlling expansion of auto- and
allo-reactive T cells. The serine/threonine kinase DRAK2 is a negative regulator of T cell receptor (TCR) signaling
and has been found to set the threshold for the activation of naïve T cells and selected thymocytes. We have
determined that Drak2-/- (D2-/-) mice are resistant to experimental autoimmune encephalomyelitis (EAE), an
autoimmune demyelinating disease that resembles MS. D2-/- mice are similarly resistant to type I diabetes, an
autoimmune disease in which T cells attack insulin producing pancreatic beta cells. D2-/- T cells also possess a
defect in rejecting allogeneic transplants. Importantly, D2-/- mice retain functional immunity against a host of
viruses. Pharmacologic blockade of DRAK2 signaling may thus afford a unique approach to treat organ specific
autoimmune diseases such as MS and may also prolong the survival of allografts. Thus, the need for powerful
immune suppressive drugs that are themselves highly problematic when used for long-term control of
autoimmune symptoms may be overcome. Although the complete basis for this enigmatic role for DRAK2
remains to be discerned, we have discovered that encephalitogenic D2-/- T cells possess significant survival
defects that prevent the elaboration of EAE. In recent studies, we have also determined that DRAK2 contributes
to the differentiation of helper T cells (Th) such that in its absence, a greater fraction of tolerogenic CD4+/FoxP3+
regulatory T cells (Treg) are produced both under steady state conditions, and following activation of naïve
CD4+/CD25--depleted T cells.
 In studies proposed in this new application, we seek to investigate the means by which DRAK2
contributes to the metabolism of activated effector T cells. We have found that D2-/- T cells are unable to properly
coordinate mitochondrial metabolism and die through intrinsic apoptosis, a form of programmed cell death that
is instigated by the release of mitochondrial factors such as cytochrome C. Using a combination of protein
crosslinking and mass spectrometry, we will characterize the interaction partners of DRAK2 and determine if
these interactors are subject to DRAK2 mediated phosphorylation. We will also determine how these proteins
form complexes with DRAK2 and will determine if their phosphorylation is required for coordinated mitochondrial
metabolism, regulation of the mitochondrial permeability transition pore (mPTP) and the prevention of intrinsic
apoptosis. These studies will be highly insightful regarding the unique role(s) that DRAK2 plays in controlling
effector T cell metabolism and survival, information that will be vital to the development of therapeutics that target
DRAK2 for the treatment of autoimmune diseases such as MS and type-I diabetes, and for the prevention of
allograft rejection.

## Key facts

- **NIH application ID:** 9852594
- **Project number:** 5R21AI144823-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Craig Michael Walsh
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $183,112
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852594

## Citation

> US National Institutes of Health, RePORTER application 9852594, Regulation of T cell metabolism by DRAK2 (5R21AI144823-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9852594. Licensed CC0.

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