Discovery of micropeptides in human immune cells and systemic lupus erythematosus

Somewhere between 5 and 8% of the human genome is made up of viral trash: old pieces of viral genomes that once, long ago in evolution, infected our cells and left their DNA sequences behind like graffiti tags. Although these sequences, known as endogenous retroviruses, no longer code for the viral proteins they were once intended to build, they aren’t just inert stretches of our genome. Endogenous retroviruses have been implicated in our genome’s evolution and in various diseases, including lupus, a devastating autoimmune disease in which a patient’s immune system attacks their own organs. Sarah Slavoff, Ph.D., Grace Chen, Ph.D. and Joseph Craft, M.D. are leading a project to explore the hypothesis that human endogenous retroviruses produce tiny difficult-to-detect proteins known as micropeptides that could drive lupus. The team will look for the presence of micropeptides from these retroviruses in human immune cells and then will study blood samples from lupus patients to determine if their levels or roles change between healthy immune cells and those in autoimmune disease. Their work could uncover the reasons for a heretofore mysterious disease.  

Affiliated Investigators

Sarah Slavoff, Ph.D.

Yale University

Dr. Sarah Slavoff is an Associate Professor in the Departments of Chemistry and Molecular Biophysics and Biochemistry at Yale University. She received her Ph.D. in Biological Chemistry at the Massachusetts of Institute of Technology working with Alice Ting, where she developed technologies for enzymatic biotinylation and fluorophore labeling of interacting proteins. During her NIH postdoctoral fellowship with Alan Saghatelian at Harvard University, Dr. Slavoff developed the first high-sensitivity liquid chromatography-mass spectrometry peptidomic technology for detection of micropeptides, revealing nearly 100 previously undiscovered, short human genes. She subsequently identified MRI-2/CYREN, a micropeptide that regulates non-homologous end joining, the major pathway of DNA double strand break repair in human cells. Since starting her independent research group at Yale in 2014, Dr. Slavoff has continued to innovate new quantitative and chemoproteomic approaches for functional micropeptide discovery, as well as cellular and molecular characterization of micropeptides. Her group was the first to demonstrate that a micropeptide, alt-RPL36, regulates the PI3K signaling pathway, and that phosphorylation of the NBDY micropeptide regulates formation of membraneless organelles in human cells. Dr. Slavoff was named a Searle Scholar in 2016, and received a 2019 Smith Family Foundation Odyssey Award and a 2020 Yale University Arthur Greer Memorial Prize for Outstanding Scholarly Research or Publication.

Grace Chen, Ph.D.

Yale University

Grace Chen is an Assistant Professor in the Department of Immunobiology at Yale University. She received her Ph.D. in Chemical Biology from Harvard University, where she identified novel RNA modifications using analytical chemistry and chemical biology approaches in the laboratory of Dr. David Liu. After graduating, she joined the laboratory of Dr. Howard Chang at Stanford University for her postdoctoral fellowship. During her postdoctoral training, she developed tools to study circular RNAs and elucidated how cells differentiate between self and non-self circular RNAs. Her work demonstrated how RNA modifications regulate the proteins that interact with circular RNAs and either promote or prevent immune stimulation. Now at Yale University, Dr. Chen continues to explore the functions and regulations of RNAs in health and disease. A major focus of the Chen lab is to understand how different features of RNAs affect their activity, translation, stability, and the induction or evasion of immune activation, with the goal of developing therapies to treat autoimmune diseases and cancer based on targeting specific aspects of RNA. She is the recipient of the Rita Allen Foundation Scholars Award and the NIH R35 grant.

Joe Craft, Ph.D.

Yale

Dr. Joe Craft, Paul B. Beeson Professor of Medicine and Professor of Immunobiology at Yale, is a graduate of the University of North Carolina School of Medicine. He did postgraduate training in internal medicine, rheumatology and immunology at Yale, and directs a laboratory devoted to understanding of systemic lupus erythematosus (SLE, lupus) and host responses to viral pathogens. Dr. Craft is a two-time NIH MERIT Awardee, recipient of the Yale Bohmfalk Basic Science Teaching Prize, and an elected Fellow of American Association for Advancement of Science. He directs the Yale Investigative Medicine MD to PhD Program and is Director of the Colton Center for Autoimmunity at Yale. Dr. Craft is chair of the Board of Lupus Therapeutics of the Lupus Research Alliance, and past chair of the Board of Scientific Counselors at NIAMS and of the Scientific Advisory Board of the Lupus Research Alliance.