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J. Cell Biol.,
Volume 139, Number 3, November 3, 1997 749-758
* Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606, Japan; Breakdown of microvilli is a common early
event in various types of apoptosis, but its molecular
mechanism and implications remain unclear. ERM
(ezrin/radixin/moesin) proteins are ubiquitously expressed microvillar proteins that are activated in the cytoplasm, translocate to the plasma membrane, and
function as general actin filament/plasma membrane
cross-linkers to form microvilli. Immunofluorescence microscopic and biochemical analyses revealed that, at
the early phase of Fas ligand (FasL)-induced apoptosis
in L cells expressing Fas (LHF), ERM proteins translocate from the plasma membranes of microvilli to the cytoplasm concomitant with dephosphorylation. When
the FasL-induced dephosphorylation of ERM proteins
was suppressed by calyculin A, a serine/threonine
protein phosphatase inhibitor, the cytoplasmic translocation of ERM proteins was blocked. The interleukin-1 First Department of Internal
Medicine, Nagoya University School of Medicine, Nagoya 466, Japan; § Department of Cell Biology, Graduate School of
Biological Science, Nara Institute of Science and Technology, Ikoma 630-01, Nara, Japan; Second Department of Internal
Medicine, Osaka University Medical School, Suita, Osaka 565, Japan; ¶ Department of Genetics, Osaka University Medical
School, Suita, Osaka 565, Japan; and ** College of Medical Technology, Kyoto University, Sakyo-ku, Kyoto 606, Japan
-converting enzyme (ICE) protease inhibitors
suppressed the dephosphorylation as well as the cytoplasmic translocation of ERM proteins. These findings
indicate that during FasL-induced apoptosis, the ICE
protease cascade was first activated, and then ERM
proteins were dephosphorylated followed by their cytoplasmic translocation, i.e., microvillar breakdown.
Next, to examine the subsequent events in microvillar
breakdown, we prepared DiO-labeled single-layered
plasma membranes with the cytoplasmic surface freely exposed from FasL-treated or nontreated LHF cells.
On single-layered plasma membranes from nontreated
cells, ERM proteins and actin filaments were densely
detected, whereas those from FasL-treated cells were
free from ERM proteins or actin filaments. We thus concluded that the cytoplasmic translocation of ERM
proteins is responsible for the microvillar breakdown at
an early phase of apoptosis and that the depletion of
ERM proteins from plasma membranes results in the
gross dissociation of actin-based cytoskeleton from
plasma membranes. The physiological relevance of this
ERM protein-based microvillar breakdown in apoptosis will be discussed.
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