TY - JOUR
T1 - How the Membrane Attack Complex Damages the Bacterial Cell Envelope and Kills Gram-Negative Bacteria
AU - Doorduijn, Dennis J.
AU - Rooijakkers, Suzan H.M.
AU - Heesterbeek, Dani A.C.
N1 - Funding Information:
The authors were funded by a European Research Council (ERC) starting grant (639209-ComBact, to S.H.M.R). The authors would also like to acknowledge Bart Bardoel for proofreading the manuscript.
Publisher Copyright:
© 2019 The Authors. BioEssays Published by Wiley Periodicals, Inc.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - The human immune system can directly lyse invading micro-organisms and aberrant host cells by generating pores in the cell envelope, called membrane attack complexes (MACs). Recent studies using single-particle cryoelectron microscopy have revealed that the MAC is an asymmetric, flexible pore and have provided a structural basis on how the MAC ruptures single lipid membranes. Despite these insights, it remains unclear how the MAC ruptures the composite cell envelope of Gram-negative bacteria. Recent functional studies on Gram-negative bacteria elucidate that local assembly of MAC pores by surface-bound C5 convertase enzymes is essential to stably insert these pores into the bacterial outer membrane (OM). These convertase-generated MAC pores can subsequently efficiently damage the bacterial inner membrane (IM), which is essential for bacterial killing. This review summarizes these recent insights of MAC assembly and discusses how MAC pores kill Gram-negative bacteria. Furthermore, this review elaborates on how MAC-dependent OM damage could lead to IM destabilization, which is currently not well understood. A better understanding on how MAC pores kill bacteria could facilitate the future development of novel strategies to treat infections with Gram-negative bacteria.
AB - The human immune system can directly lyse invading micro-organisms and aberrant host cells by generating pores in the cell envelope, called membrane attack complexes (MACs). Recent studies using single-particle cryoelectron microscopy have revealed that the MAC is an asymmetric, flexible pore and have provided a structural basis on how the MAC ruptures single lipid membranes. Despite these insights, it remains unclear how the MAC ruptures the composite cell envelope of Gram-negative bacteria. Recent functional studies on Gram-negative bacteria elucidate that local assembly of MAC pores by surface-bound C5 convertase enzymes is essential to stably insert these pores into the bacterial outer membrane (OM). These convertase-generated MAC pores can subsequently efficiently damage the bacterial inner membrane (IM), which is essential for bacterial killing. This review summarizes these recent insights of MAC assembly and discusses how MAC pores kill Gram-negative bacteria. Furthermore, this review elaborates on how MAC-dependent OM damage could lead to IM destabilization, which is currently not well understood. A better understanding on how MAC pores kill bacteria could facilitate the future development of novel strategies to treat infections with Gram-negative bacteria.
KW - C5 convertases
KW - complement
KW - Gram-negative bacteria
KW - membrane attack complexes
KW - serum bactericidal activities
UR - https://www.scopus.com/pages/publications/85071777297
U2 - 10.1002/bies.201900074
DO - 10.1002/bies.201900074
M3 - Review article
C2 - 31452228
AN - SCOPUS:85071777297
SN - 0265-9247
VL - 41
JO - BioEssays
JF - BioEssays
IS - 10
M1 - 1900074
ER -