Lonnie P Lybarger
Associate Professor, Cellular and Molecular Medicine
Associate Professor, BIO5 Institute
Associate Professor, Immunobiology
Primary Department
Department Affiliations
(520) 626-1044
Research Interest
Lonnie Lybarger, PhD, is an Associate Professor in the Department of Cellular and Molecular Medicine within the College of Medicine at the University of Arizona. Dr. Lybarger’s research program focuses on the mechanisms that regulate the activation of immune responses. In particular, his group studies a process known as antigen presentation, which is central to many aspects of the immune response against pathogens and tumors. This work includes detailed analyses of the cell biology of antigen presentation, as well as the study of its impact on immune responses. Recently, Dr. Lybarger has begun to study the critical link between antigen presentation and the regulation of metabolic homeostasis, with relevance to conditions such as type II diabetes.Research in the Lybarger lab has been funded by grants from State and National agencies. He has been an author/co-author on ≈35 original research reports, with his major contributions coming in the field of antigen presentation. Many of these reports involve collaborations within the University of Arizona and with colleagues at other institutions. Dr. Lybarger has served as a reviewer for University and National granting agencies, as well as reviewing for many research journals. In addition, Dr. Lybarger has served as a primary research advisor to a number of graduate and undergraduate students, while contributing to the classroom instruction of medical and graduate students.

Publications

Bhagwandin, C., Ashbeck, E. L., Whalen, M., Szajman, A., Truong, S. M., Wertheim, B. C., Klimentidis, Y. C., Ishido, S., Renquist, B. J., & Lybarger, L. P. (2018). The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner. PlosOne.
BIO5 Collaborators
Yann C Klimentidis, Lonnie P Lybarger
Lybarger, L., Corcoran, K., Wang, X., & Lybarger, L. P. (2009). Adapter-mediated substrate selection for endoplasmic reticulum-associated degradation. The Journal of biological chemistry, 284(26).

During endoplasmic reticulum (ER)-associated degradation (ERAD), a relatively small number of ubiquitin ligases (E3) must be capable of ubiquitinating an assortment of substrates diverse in both structure and location (ER lumen, membrane, and/or cytosol). Therefore, mechanisms that operate independently of primary sequence determinants must exist to ensure specificity during this process. Here we provide direct evidence for adapter-mediated substrate recruitment for a virus-encoded ERAD E3 ligase, mK3. Members of an ER membrane protein complex that normally functions during major histocompatibility complex class I biogenesis in the immune system are required for mK3 substrate selection. We demonstrate that heterologous substrates could be ubiquitinated by mK3 if they were recruited by these ER accessory molecules to the proper position relative to the ligase domain of mK3. This mechanism of substrate recruitment by adapter proteins may explain the ability of some E3 ligases, including cellular ERAD E3 ligases, to specifically target the ubiquitination of multiple substrates that are unrelated in sequence.

Lybarger, L., Ordaz, M. L., Larmonier, N., & Lybarger, L. P. (2010). DC-expressed MHC class I single-chain trimer-based vaccines prime cytotoxic T lymphocytes against exogenous but not endogenous antigens. Cellular immunology, 262(2).

The poor immunogenicity of many tumors can be partly explained by the inefficiency of the MHC class I peptide presentation pathway. MHC-I-based single-chain trimers (SCT) represent a new class of molecules with the potential to overcome this limitation. We here evaluated the ability of SCT presenting a melanoma antigen peptide (TRP-2) to prime cytotoxic T lymphocyte (CTL) responses in mice when given as DNA vaccines via Gene Gun or when expressed by dendritic cells. The SCT was unable to induce detectable priming or significant anti-tumor activity of CTL using either vaccination strategy, whereas control SCT (with an exogenous peptide) primed strong responses. This study thus provides the first data related to the use of SCT in combination with DC and their application toward self antigens and suggest this potent technology, alone, is insufficient to overcome self tolerance.

Lybarger, L., Jabbour, M., Campbell, E. M., Fares, H., & Lybarger, L. P. (2009). Discrete domains of MARCH1 mediate its localization, functional interactions, and posttranscriptional control of expression. Journal of immunology (Baltimore, Md. : 1950), 183(10).

Within APCs, ubiquitination regulates the trafficking of immune modulators such as MHC class II and CD86 (B7.2) molecules. MARCH1 (membrane-associated RING-CH), a newly identified ubiquitin E3 ligase expressed in APCs, ubiquitinates MHC class II, thereby reducing its surface expression. Following LPS-induced maturation of dendritic cells, MARCH1 mRNA is down-regulated and MHC class II is redistributed to the cell surface from endosomal compartments. Here, we show that MARCH1 expression is also regulated at the posttranscriptional level. In primary dendritic cell and APC cell lines of murine origin, MARCH1 had a half-life of

Lybarger, L., Corcoran, K., Jabbour, M., Bhagwandin, C., Deymier, M. J., Theisen, D. L., & Lybarger, L. P. (2011). Ubiquitin-mediated regulation of CD86 protein expression by the ubiquitin ligase membrane-associated RING-CH-1 (MARCH1). The Journal of biological chemistry, 286(43).

The activation of naïve T cells requires antigen presentation by dendritic cells (DCs), and the process of antigen presentation is regulated over the course of DC maturation. One key aspect of this regulation is the cell surface up-regulation upon DC maturation of peptide·MHC-II complexes and the costimulatory molecule CD86. It is now clear that these critical induction events involve changes in ubiquitin-dependent trafficking of MHC-II and CD86 by the E3 ligase membrane-associated RING-CH-1 (MARCH1). Although ubiquitin-dependent trafficking of MHC-II has been well characterized, much less is known regarding the post-transcriptional regulation of CD86 expression. Here, we examined the physical and functional interaction between CD86 and MARCH1. We observed that CD86 is rapidly endocytosed in the presence of MARCH1 followed by lysosome-dependent degradation. Furthermore, we found that the association between CD86 and MARCH1 was conferred primarily by the transmembrane domains of the respective proteins. In contrast to MHC-II, which has a single, conserved ubiquitin acceptor site in the cytosolic domain, we found that multiple lysine residues in the cytosolic tail of CD86 could support ubiquitination consistent with the relative lack of sequence conservation across species within the CD86 cytosolic domain. These findings suggest that MARCH1 recruits multiple substrates via transmembrane domain-mediated interactions to permit substrate ubiquitination in the face of diverse cytosolic domain sequences.