# Role of the CCC complex in immune function

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $364,500

## Abstract

PROJECT SUMMARY
The transcription factor NF-κB is responsible for inducing the expression of a plethora of genes that are
essential for immune function. The signaling pathways that activate the NF-κB system have been extensively
studied and require the degradation of inhibitory factors known as ‘classical’ IκB proteins (IκB-α, -β, and -ε). In
addition, work supported by this grant uncovered that degradation of NF-κB subunits plays an essential part in
terminating pro-inflammatory gene expression. These degradation events are dependent on specific members
of the COMMD protein family: COMMD1 is needed for optimal degradation of NF-κB/RelA, and in a similar
fashion, optimal degradation of IκB is dependent on COMMD8. In more recent work, we discovered that
COMMD proteins are integral components of a regulatory complex that controls endosomal protein sorting: the
COMMD/CCDC22/CCDC93 or CCC complex. A variety of proteins that traverse endosomes depend on this
complex to be trafficked properly to their final destination. Preliminary data now demonstrate that in myeloid
cells, COMMD proteins not only regulate NF-κB signaling, but also play an intrinsic role in phagocytosis. In
vivo, inactivation of this system in myeloid cells leads to increased bacterial penetration in the colonic mucosa,
which promotes colon adenoma formation in genetically susceptible mice. Based on these observations, we
hypothesize that the CCC complex regulates key aspects of myeloid cell immune function, including NF-κB
signaling, phagocytosis, and the roles of these cells during tumor development. The overall goal of this project
is to examine the role of the CCC complex in immune function at three levels of increasing system complexity
through these specific aims: (1) To evaluate the role of endosomes in NF-κB signaling: Our data indicate that
loss of CCC complex subunits leads to disruption in IκB degradation. In this aim we will evaluate the
hypothesis that the CCC complex is responsible for ‘organizing’ IκB turnover on endosomal membrane
surfaces. (2) To examine the mechanism by which the CCC complex regulates the phagocytic process:
Preliminary studies indicate that the CCC complex localizes to phagolysosomes and we find that Commd1
deletion in myeloid cells impairs the phagocytic elimination of bacteria. In this aim we will systematically assess
potential mechanisms by which the CCC complex might assist the phagocytic process. (3) To examine the role
of the CCC complex in intestinal immunity and cancer progression: Preliminary studies in the myeloid-specific
Commd1 knockout mice identified greater penetration of commensal bacteria into the lamina propria of the
colon. Unexpectedly, colon adenoma formation is greatly enhanced in genetically susceptible mice (ApcMin
mice) upon deletion of Commd1 in myeloid cells and this is dependent on intestinal bacteria. In this Aim we will
test the hypothesis that microbial elimination by myeloid cells in the intestinal lamina propria can...

## Key facts

- **NIH application ID:** 9852436
- **Project number:** 5R01DK073639-12
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ezra Burstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,500
- **Award type:** 5
- **Project period:** 2007-02-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852436

## Citation

> US National Institutes of Health, RePORTER application 9852436, Role of the CCC complex in immune function (5R01DK073639-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852436. Licensed CC0.

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