The transcription factor NF-?B is responsible for inducing the expression of a plethora of genes that are essential for immune function. The signaling pathways that activate the NF-?B system have been extensively studied and require the degradation of inhibitory factors known as ?classical? I?B proteins (I?B-?, -?, and -?). In addition, work supported by this grant uncovered that degradation of NF-?B 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-?B/RelA, and in a similar fashion, optimal degradation of I?B 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-?B 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-?B 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-?B signaling: Our data indicate that loss of CCC complex subunits leads to disruption in I?B degradation. In this aim we will evaluate the hypothesis that the CCC complex is responsible for ?organizing? I?B 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 affect tumor development. Altogether, this proposal is intended to provide insights that have the potential of shifting our current understanding of critical pathways in immune function and human disease.
Immune defence involves a variety of genetically programmed mechanisms by which cells recognize and respond to invasive organisms and other forms of injury. The resulting response leads to inflammation, which under physiologic conditions, protects tissues from further damage and promotes repair. However, persistent inflammation is a common element in human disease, leading to tissue destruction and an increased risk for cancer. This proposal is focused on pathways that control innate immunity and inflammation, and their role in cancer development.
| Miyata, Naoteru; Morris, Lindsey L; Chen, Qing et al. (2018) Microbial Sensing by Intestinal Myeloid Cells Controls Carcinogenesis and Epithelial Differentiation. Cell Rep 24:2342-2355 |
| Wang, Jing; Fedoseienko, Alina; Chen, Baoyu et al. (2018) Endosomal receptor trafficking: Retromer and beyond. Traffic 19:578-590 |
| Alekhina, Olga; Burstein, Ezra; Billadeau, Daniel D (2017) Cellular functions of WASP family proteins at a glance. J Cell Sci 130:2235-2241 |
| Starokadomskyy, P; Sifuentes-Dominguez, L; Gemelli, T et al. (2017) Evolution of the skin manifestations of X-linked pigmentary reticulate disorder. Br J Dermatol 177:e200-e201 |
| McNally, Kerrie E; Faulkner, Rebecca; Steinberg, Florian et al. (2017) Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat Cell Biol 19:1214-1225 |
| Jia, Da; Zhang, Jin-San; Li, Fang et al. (2016) Structural and mechanistic insights into regulation of the retromer coat by TBC1d5. Nat Commun 7:13305 |
| Starokadomskyy, Petro; Gemelli, Terry; Rios, Jonathan J et al. (2016) DNA polymerase-? regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. Nat Immunol 17:495-504 |
| Bartuzi, Paulina; Billadeau, Daniel D; Favier, Robert et al. (2016) CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nat Commun 7:10961 |
| Sun, Qingxiang; Chen, Xueqin; Zhou, Qiao et al. (2016) Inhibiting cancer cell hallmark features through nuclear export inhibition. Signal Transduct Target Ther 1:16010 |
| Li, Haiying; Koo, Yeon; Mao, Xicheng et al. (2015) Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling. J Cell Biol 211:605-17 |
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