Inflammation is a genetically programmed response to cellular stress that plays a critical role in tissue injury and repair. Within this very broad field, the work of the lab is concentrated on 3 distinct areas: (1) regulation of the endolysosomal system, (2) role of enteroendocrine cells in host-microbial interactions, and (3) genetic determinants of abnormal inflammatory responses in humans.”
Our earliest work was focused on the regulation of the transcription factor NF-κB, which plays a central role in the inflammatory cascade. In particular, we investigated pathways that mediate the termination of NF-κB activity, leading to the identification of COMMD1 (formerly Murr1) as a negative regulator of the NF-κB pathway (Nature, 2003). This led us to identify that it plays a key role in terminating NF-κB dependent transcription through ubiquitination (EMBO J, 2007). Furthermore, we identified that these steps are regulated by phosphorylation and acetylation of the NF-κB subunits (Genes & Dev, 2008; Oncogene, 2012). Altogether, these studies uncovered key aspects of this critical pathway which are now recognized as canonical components of NF-κB regulation.”
Our initial work led us to the discovery of the COMMD protein family, which is defined by a unique domain (JBC, 2005). 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 complex known as the CCC protein assembly (MBoC, 2015). Thereafter, we identified that CCC regulates a novel cargo recognition system that we named Retriever (Nat Cell Bio, 2017) and most recently we described that CCC works through the regulation of endosomal levels of phosphoinositide-3-phoshate (Nat Comm, 2019). Building on these discoveries, we were able to produce a high-resolution structure of Retriever, and an AlphaFold Multimer molecular model for its interaction with CCC (Nat Struct Mol Bio, 2024). This work is supported by NIH R01DK107733, and pending additional support from NIH R01HL179813.
Arising from genetic discoveries in patients with ulcerative colitis, we began investigating the role of enteroendocrine cells in intestinal homeostasis. We generated a model of colonic deficiency of enteroendocrine cells and uncovered that these cells regulate microbial metabolism and community composition, with profound effects on host appetite and weight regulation (Nat Metabolism, 2024). This work is supported by NIH R01DK130957.
In addition to molecular events involved in immune signaling, 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 (JCI, 2013). We also found that X-linked reticulate pigmentary disorder, an immunodeficiency and autoinflammatory syndrome that results in infantile ulcerative colitis, is due to mutations in the catalytic subunit of DNA polymerase-α, and in the process, we identified a surprising role for this polymerase in the interferon pathway (Nat Immunol, 2016) and in NK cell regulation (JCI Insight, 2019). Through similar efforts we identified a new mutation that results in a Mendelian form of ulcerative colitis through effects in neuroendocrine function in the GI tract (eLife, 2019).
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.
