Inflammation is a genetically programmed response to cellular stress that plays a critical role in tissue injury and repair. Not surprisingly, inflammation is linked to many human diseases. Broadly, the work in the lab is focused on uncovering basic mechanisms that control inflammatory responses, and describing their relevance in human disease, particularly inflammatory bowel disease.

Blue-one hand pointing to gene research

Termination of inflammatory responses

Research model Caption placeholder text

Earlier work in the lab focused on the regulation of the transcription factor NF-kB, which plays a central role in the inflammatory cascade. Most of the efforts to understand this pathway had been centered on the signaling steps that result in its activation. However, less attention had been placed on pathways that mediate the termination of NF-kB activity. Our earliest work was devoted to this field, leading to the identification of COMMD1 (formerly Murr1) as a negative regulator of the NF-kB pathway (a). This led us to identify that it plays a key role in terminating NF-kB dependent transcription through ubiquitination (b). Furthermore, we identified that these steps are regulated by phosphorylation and acetylation of the NF-kB subunits (c and d). This work was largely supported by NIH (R01DK073639). Altogether, these studies uncovered key aspects of this critical pathway which are now recognized as canonical components of NF-kB regulation.

Emerging from this work, the new directions we are examining are the roles of COMMD proteins in regulating immune signaling and phagocytic competency through the activities of these proteins on endosomal protein sorting.

  1. Ganesh L, Burstein E, Guha-Niyogi A, Louder M, Mascola J, Klomp LWJ, Wijmenga C, Duckett CS, Nabel GJ. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature, 426: 853-857 (2003). PMID: 14685242. **Featured, News & Views summary
  2. Maine GN, Mao X, Komarck CM, Burstein E. COMMD1 promotes the ubiquitination of NF-kB/subunits through a Cullin containing ubiquitin ligase. EMBO Journal, 26: 459-467 (2007). PMC1783443. **Featured article
  3. Mao X, Gluck N, Maine GN, Li H, Zaidi IW, Li D, Repaka A, Mayo MW, Burstein E. GCN5 is a required co-factor for a ubiquitin ligase that targets NF-kB/RelA. Genes & Development, 23: 849-861 (2009). PMC2666342.
  4. Li H, Wittwer T, Weber A, Schneider H, Moreno R, Maine GN, Kracht M, Schmitz ML, Burstein E. Regulation of NF-kB activity by competition between RelA acetylation and ubiquitination. Oncogene, 31: 611-623 (2012). PMC3183278.

Molecular genetics of altered host immune response

Other cellular functions of COMMD Proteins Caption placeholder text

In addition to an analysis of molecular events involved in NF-κB regulation, the lab investigates the genetic and molecular basis of human disorders of immune dysfunction. We demonstrated that CCDC22 is required for optimal IκB protein degradation and that mutations in this gene result in altered immune activation in humans (a). We also found that X-linked reticulate pigmentary disorder, immunodeficiency, and autoinflammatory syndrome, are due to mutations in DNA polymerase-α, and in the process, we identified a surprising role for this polymerase in the interferon pathway (b) and in NK cell regulation (c). We continue to study how Pol-a is linked to interferon regulation. Most recently, we identified a new mutation in the gene SCGN that results in a Mendelian form of ulcerative colitis (d). This gene is expressed in neuroendocrine cells where it regulates neurotransmitter and hormone release through the SNARE complex.

Additional studies inspired by the discovery of SCGN mutations led us to the development of various mouse models, including the generation of conditional deletion of enteroendocrine cells in the colon, which is uncovering new roles for these cells in host-microbiota interactions and metabolic regulation.

  1. Starokadomskyy P, Gluck N, Li H, Chen B, Wallis M, Maine GN, Mao X, Zaidi IW, Hein MY, McDonald FJ, Lenzner S, Zecha A, Ropers HH, Kuss AW, McGaughran J, Gecz J, Burstein E. CCDC22 deficiency in humans blunts activation of pro-inflammatory NF-kB signaling. Journal of Clinical Investigation, 123: 2244–2256 (2013). PMC3635737.
  2. Starokadomskyy P, Gemelli T, Rios JJ, Xing C, Wang RC, Li H, Pokatayev V, Dozmorov I, Khan S, Miyata N, Fraile G, Raj P, Xu Z, Xu Z, Ma L, Lin Z, Wang H, Yang Y, Ben-Amitai D, Orenstein N, Mussaffi H, Baselga E, Tadini G, Grunebaum E, Sarajlija A, Krzewski K, Wakeland EK, Yan N, de la Morena MT, Zinn AR, Burstein E.  DNA polymerase-α regulates type I interferon activation through cytosolic RNA: DNA synthesis. Nature Immunology, 17: 495–504 (2016). PMC4836962. **Featured article, News & Views summary. F1000 selected article.
  3. Starokadomskyy P, Wilton KM, Krzewski K, Lopez A, Sifuentes-Dominguez L, Overlee B, Chen Q, Ray A, Gil-Krzewska A, Peterson M, Kinch LN, Rohena L, Grunebaum E, Zinn AR, Grishin NV, Billadeau DD, Burstein E. NK cell defects in X-linked pigmentary reticulate disorder. Journal of Clinical Investigation Insight, 4:125688 (2019). PMID: 31672938.
  4. Sifuentes-Dominguez L, Li H, Llano E, Liu Z, Singla A, Patel AS, Kathania M, Khoury A, Norris N, Rios JJ, Starokadomskyy P, Park JY, Gopal P, Liu Q, Tan S, Chan L, Ross T, Harrison S, Venuprasad K, Baker LA, Jia D, Burstein ESCGN deficiency results in colitis susceptibility. ELife, 8: e49910 (2019). PMC6839920.

Regulation of endosomal sorting

Other cellular functions of COMMD Proteins chart Caption placeholder text

Early work on pro-inflammatory gene transcription (see below) led us to the discovery of the COMMD protein family, which is defined by a unique domain (a). Nearly at the same time as our work implicated COMMD1 in immune regulation, genetic studies identified this factor as playing a central role in copper metabolism, through unclear mechanisms. We discovered that COMMD1 regulates cellular copper through a previously unknown protein complex that controls recycling of proteins from the endosomal compartment – we identified and reported the existence of this molecular assembly known as the CCC protein complex (b). Thereafter, we identified that CCC regulates a novel cargo recognition complexed that we named Retriever (c) and most recently we described that CCC works through the regulation of endosomal levels of phosphoinositide-3-phoshate (d).

We are currently investigating how these steps regulate nutrient homeostasis through trafficking of key surface transporters and how these events are controlled by lipid phosphatases associated to the CCC complex (R01 DK107733).

  1. Burstein E, Hoberg JE, Wilkinson AS, Rumble JM, Csomos RA, Komarck CM, Maine GN, Wilkinson JC, Mayo MW, Duckett CS.  COMMD Proteins: a novel family of structural and functional homologs of MURR1.Journal of Biological Chemistry, 280: 22222-22232 (2005). PMID: 15799966.
  2. Phillips-Krawczak CA‡, Singla A‡, Starokadomskyy P, Deng Z, Osborne DG, Li H, Dick CJ, Gomez TS, Koenecke M, Zhang J-S, Dai H, Kaufmann SH, Hein MY, Wallis M, McGaughran J, Gecz J, van de Sluis B, Billadeau DD, Burstein E.  COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A.  Molecular Biology of the Cell,26: 91-103 (2015). PMC4279232.
  3. McNally KE, Faulkner R, Steinberg F, Gallon M, Ghai R, Pim D, Langton P, Pearson N, Danson CM, Nägele H, Morris LM, Singla A, Overlee BL, Heesom KJ, Sessions R, Banks L, Collins BM, Berger I, Billadeau DD, Burstein E, Cullen PJ. Retriever, a multiprotein complex for retromer-independent endosomal cargo recycling.  Nature Cell Biology, 19: 1214-1225(2017). PMC5790113.
  4. Singla A, Fedoseienko A, Giridharan SSP, Overlee BL, Lopez A, Jia D, Song J, Huff-Hardy K, Weisman L, Burstein E, Billadeau DD. Endosomal PI(3)P regulation by the CCC complex controls membrane protein recycling. Co-corresponding authors. Nature Communications, 10: 4271 (2019). 

Join Our Lab

There are frequent opportunities to join our lab. If you have an interest in the research that we are conducting and would like to be considered for a position in the lab, please send an email including CV and a letter of interest to Ezra Burstein.