Louis B. Justement, PhD

justement-louisProfessor

Dept. of Microbiology
Div. of Developmental & Clinical Immunology

Contact Information:

Office Address: SHEL 502
Phone: 205-934-1429
E-mail: lbjust@uab.edu
Websites:   School of Medicine Faculty Profile

Education:

Miami University, Oxford, Ohio 
BA, Microbiology, 1980

Ohio State University, Columbus, OH 
MS, Microbiology, 1982

Ohio State University 
PhD, Microbiology, 1985

Post-Graduate Training:

National Jewish Medical Research Center, Denver, CO 
Postdoctoral Fellow, Depts. of Medicine and Pediatrics, 1985-90

Research Description:

Analysis of the Molecular and Functional Role of the Adaptor Protein HSH2
Studies are ongoing to elucidate the functional role that the adaptor protein HSH2 plays in regulating B cell biology.  HSH2 is selectively expressed in cells of the B lineage and its expression is up-regulated in response to agonists that promote B cell survival and differentiation, including CD40L, BLyS, LPS and CpG DNA.  Studies have demonstrated that HSH2 is able to block BCR-induced apoptosis in the WEHI-231 B cell line, suggesting that this adaptor is expressed as part of a pro-survival program that is triggered by a range of stimuli.  Although HSH2 has been shown to block mitochondrial depolarization in WEHI-231 cells in response to BCR cross-linking, it has little effect on BCR-proximal signaling. Interestingly, HSH2 has been found to interact with the mitochondrial outer membrane protein HAX-1, which has also been shown to function as a pro-survival protein. Thus, it is possible that HSH2 is involved in regulating distal signal transduction processes that control mitochondrial stability.  Recent studies using transgenic mice have revealed that HSH2 does indeed play a critical role in regulating terminal differentiation of B cells into antibody secreting plasma cells.  Based on these observations, it is likely that HSH2 is involved in regulating the survival and differentiation of B cells.  Future studies will be conducted to:

  • Identify important regions/motifs of HSH2 that are involved in its pro-survival function
  • Identify the proteins that interact with HSH2 in B lymphocytes and assess their functional importance
  • Generate transgenic and conditional knockout mice to examine the importance of HSH2 in regulation of B cell development, activation and differentiation

Analysis of the Molecular and Functional Role of the Transmembrane Receptor Trem-Like Transcript 2 (TLT2)
The genes encoding mouse and human TLT2 were cloned in our laboratory.  Subsequent experiments demonstrated that TLT2 is expressed on B cells, neutrophils and macrophages.  With respect to the B lineage, TLT2 is expressed early during development, prior to the BCR and can be detected on both fetal liver- and bone marrow-derived B cell progenitors.  Although TLT2 is expressed on all B cells in the periphery, its level is higher on transitional, marginal zone and B-1 B cells when compared to follicular B cells.  Expression of TLT2 can be detected on peritoneal and alveolar macrophages but not on monocytes in the blood.  Finally, TLT2 is expressed on neutrophils and neutrophil progenitors.  Importantly, TLT2 is significantly up-regulated on macrophages and neutrophils in response to inflammatory stimuli such as LPS or Staphylococcal superantigens.  Neutrophils also contain large pools or preformed TLT2 in their granules that are rapidly released in response to activating stimuli such as FMLP or PMA.  Thus, TLT2 is likely to play an important role in the innate immune response and is likely to functionally bridge components of the innate response with the adaptive response.  Future studies will be conducted to:

  • Assess the functional role played by TLT2 in immune responses to infectious organisms; conditional knockout mice will be generated for these studies
  • Identify the ligand(s) for TLT2 using several molecular and biochemical approaches
  • Identify interacting signal transduction proteins and their associated pathways that mediate the functional effects of TLT2 on immune cells

Analysis of Virulence Factors Produced by Mycobacterium tuberculosis
Mycobaterium tuberculosis (MTb) is a serious world-wide pathogen that has the ability to survive within host phagocytic cells such as macrophages (MØ).  It has been shown that virulent strains of MTb actually secrete a wide range of proteins or virulence factors that presumably alter host cell function.  Studies are ongoing to examine the functional role of two secreted virulence factors produced by MTb.  The first protein being studied is a protein tyrosine phosphatase called mPtpb.  This phosphatase is secreted by MTb into the host MØ where it alters host cell function presumably by dephosphorylating one or more substrates.  Ongoing studies in the lab are designed to:

  • Identify the mechanism responsible for secretion of mPtpb from MTb.
  • Identify the subcellular location of mPtpb in MØ as well as host cell proteins that interact with the phosphatase
  • Determine the effect that mPtpb has on MØ function

Studies have determined that mPtpb interacts with another protein that is secreted by MTb called enhanced intracellular survival (Eis) protein.  Analysis of Eis structure suggests that this protein may function as an acetyltransferase.  Recent work in our laboratory has confirmed that Eis is indeed an acetyltransferase enzye that can acetylate histone.  Thus it possible that Eis regulates transcription in host MØ  through its ability to acetylate one or more substrates in the cytoplasm or nucleus.  Studies are being conducted to:

  • Study Eis acetyltransferase enzyme activity
  • Identify substrates in MØ that are acetylated by Eis
  • Determine the functional effect that acetylation of specific substrates has on MØ function

Publications

DRC Membership Category:

Affiliate