U.S. Department of Health and Human Services
Harris Bernstein

 Contact Info

Tel: 301-402-4770
Email: harris_bernstein@nih.gov

 Select Experience

  • Ph.D.Massachusetts Institute of Technology1987
  • B.A.Harvard University1980

 Related Links


Harris D. Bernstein, Ph.D.

Chief, Genetics and Biochemistry BranchProtein Biogenesis Section
  • Microbiology/Infectious diseases (non-viral)
  • Molecular Biology/Biochemistry

Research Summary

Research Goal

Our goal is to understand how proteins are transported across the cell membranes of both pathogenic and nonpathogenic bacteria.

Current Research

My laboratory has a long-standing interest in understanding how proteins are transported across the cell membranes of both pathogenic and nonpathogenic bacteria.

In one project we are investigating the mechanism by which pathogenic Gram-negative bacteria secrete proteins via the autotransporter (or type V) pathway. Autotransporters are proteins that contain two domains, a large N-terminal extracellular domain (passenger domain) and a C-terminal β barrel domain (β domain) that is embedded in the outer membrane. The passenger domains of different members of the autotransporter superfamily play a variety of roles in pathogenesis. In some cases they function as adhesins, but in other cases they are cleaved from the cell surface and function as soluble virulence factors. After autotransporters are translocated across the cytoplasmic membrane by the Sec machinery, the passenger domain is transported across the outer membrane by an unknown mechanism. It was originally proposed that the passenger domain is secreted through a channel formed by the domain to which it is covalently linked (hence the name “autotransporter”).Our recent results are inconsistent with this proposal, however, and suggest that the Bam complex, a heterooligomer that promotes the integration of β barrel proteins into the outer membrane, plays a key role in passenger domain secretion.

In a second project we are studying the regulation of expression of secA, a gene that encodes a major component of the bacterial Sec machinery. Expression of this gene is regulated at the level of translation by “ribosome stalling” or “translation arrest.” SecA is in an operon with secM, a gene that encodes a small secreted protein. When the secretion burden of the cell rises, the synthesis of the SecM protein stalls shortly before ribosomes reach the termination codon. Ribosome stalling alters the secondary structure of the secM-secA mRNA and leads to a concomitant increase in secA synthesis. Our results indicate that the recognition of a secM sequence motif inside the ribosome tunnel causes ribosome stalling. We are currently trying to understand how RNA and protein components of the ribosome tunnel recognize this motif and how detection of the motif generates a signal that alters ribosome function. We believe that elucidation of the mechanism of secM stalling will yield insights into other ribosome stalling phenomena that have been observed in bacteria, fungi, and higher eukaryotic cells.

Applying our Research

Our work may lead to the development of novel strategies to inhibit autotransporter secretion and thereby attenuate bacterial virulence. Furthermore, our work may accelerate the development of vaccines against specific bacterial pathogens. Autotransporters are excellent vaccine candidates because they contain a large extracellular domain. One autotransporter (pertactin) is already in use in pertussis vaccines. Finally, our work may lead to improvements in “autodisplay” technology, a method in which autotransporters are used for the cell surface presentation of heterologous peptides or proteins. Autodisplay has proven to be a valuable alternative to phage-display technology and may ultimately be useful as a method to present antigens to induce immune protection.