Harris D. Bernstein, Ph.D.

Senior Investigator

Protein Biogenesis Section, Genetics and Biochemistry Branch


Building 5, Room B120
5 Memorial Drive
Bethesda, MD 20814



Research Topics

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 protein secretion by the Bacteroides, a genus of experimentally tractable Gram-negative bacteria that are highly abundant in the human gut microbiome. Although recent studies have suggested that these organisms influence human health significantly, their biology remains poorly understood. We recently found that one member of the Bacteroides genus, B. fragilis, utilizes a very different range of secretion strategies than well characterized Gram-negative bacteria such as E. coli. B. fragilis lacks several of the secretion pathways found in E. coli, and unlike E. coli transports a large number of lipoproteins to the cell surface. We also found that B. fragilis secretes a variety of unique proteins of unknown function. Presumably many of these proteins play important roles in colonization, persistence or communication with other microorganisms. By studying protein secretion in the Bacteroides we hope to gain insight into the remarkable ability of these organisms to thrive in a complex and potentially hostile environment.

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. Our work may also 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. Finally, our work on Bacteroides may facilitate the construction of genetically engineered strains that secrete beneficial proteins into the gut.


  • Ph.D., Massachusetts Institute of Technology, 1987
  • B.A., Harvard University, 1980

Selected Publications

  1. Pavlova O, Peterson JH, Ieva R, Bernstein HD. Mechanistic link between β barrel assembly and the initiation of autotransporter secretion. Proc Natl Acad Sci U S A. 2013;110(10):E938-47.

  2. Bernstein HD. Cell biology: All clear for ribosome landing. Nature. 2012;492(7428):189-91.

  3. Ieva R, Tian P, Peterson JH, Bernstein HD. Sequential and spatially restricted interactions of assembly factors with an autotransporter beta domain. Proc Natl Acad Sci U S A. 2011;108(31):E383-91.

  4. Kang'ethe W, Bernstein HD. Charge-dependent secretion of an intrinsically disordered protein via the autotransporter pathway. Proc Natl Acad Sci U S A. 2013;110(45):E4246-55.

  5. Roman-Hernandez G, Peterson JH, Bernstein HD. Reconstitution of bacterial autotransporter assembly using purified components. Elife. 2014;3:e04234.

This page was last updated on July 21st, 2015