6 DECEMBER 2013 VOL 342 SCIENCE www.sciencemag.org 1178
PERSPECTIVES
Dangers of Being Thin and Weak
GEOPHYSICS
Kelin Wang1 and Masataka Kinoshita2
Ocean drilling data show that the large trench-breaching rupture of the 2011 Tohoku–Oki
earthquake occurred along a thin and weak fault zone.
investigated whether T lymphocytes use the
Hh signaling pathway.
Hh signaling involves the ligand, Hh; its
cell surface receptor, Patched (Ptch); and
another transmembrane protein, Smoothened (Smo). In the absence of Hh, Ptch functions as an inhibitor of Smo. Hh binding to
Ptch releases Smo, allowing it to be transported to the tip of the cilium. This activates
the Gli family of transcription factors to control genes involved in proliferation, development, and pattern formation (5); activates
the RAC guanosine triphosphatase to modify
actin important for cell migration and dendritic spine formation (6, 7); and induces a
metabolic switch to glycolysis (8).
De la Roche et al. show that mouse naïve
T cells express all components of the Hh
signaling pathway and that Gli expression
increased over the course of several days
in response to T cell receptor activation.
Gli1 induces its own expression (2), so an
increase in Gli1 is indicative of Hh signaling. Hh appears to stimulate Ptch in the same
cell, as both ligand and receptor are found
together in secretory vesicles. Ptch signaling only occurs in the vesicle as cells did not
respond to exogenous Hh. Imaging showed
that these vesicles are distinct from the late
endosomes that contained internalized Smo.
This indicates that Hh binds to its cognate
receptor within the same T cell. Moreover,
activation of the T cell receptor (and presumably Hh signaling) increased Hh production
and induced the translocation of Smo to the
immunological synapse. The absence of Smo
or treatment of T cells with inhibitors of the
Hh signaling pathway attenuated the ability
of cytotoxic T cells to kill target cells in vitro.
De la Roche et al. propose that the T cell
immunological synapse functions as a sur-
rogate cilium. The immunological synapse
is a specialized organization of proteins at
the contact surface between a T cell and an
antigen-presenting cell. It is composed of an
outer ring that is rich in actin and adhesion
proteins (integrins), and a central region
that is free of actin, where secretion occurs.
Because the MTOC makes contacts with the
membrane in this central area, the authors
suggest that the center of the synapse func-
tions as the lymphocyte equivalent of a cil-
ium. Actin clearance from the synapse and
MTOC polarization toward the synapse were
impaired in T cells lacking Smo. Rac-medi-
ated actin remodeling is also controlled by
Hh (6, 7), and de la Roche et al. found that
Rac expression increased in a Smo-depen-
dent manner. The observation that Smo relo-
cates to the immunological synapse follow-
ing T cell receptor activation with antigen-
presenting cells is consistent with the role of
the synapse as a cilium surrogate.
Several aspects of the pathway described
by de la Roche et al. are distinct from the
canonical Hh signaling pathway, suggesting
that further clarification is needed (see the
figure). Hh is usually secreted and functions
in a concentration gradient, but the pathway
described by the authors occurs within a single
cell and is therefore not dependent on a gradient. Because Smo and Ptch are localized in
distinct vesicles, how Ptch regulates Smo and
whether translocation of Smo to the membrane
requires intraflagellar transport proteins is
unclear. T cell receptor signaling increased
their expression but did not enhance colocal-ization of Ptch and Hh in secretory vesicles,
so why activation of the Hh pathway is not
constitutive is not clear. Because cytotoxic T
cells use secretory lysosomes to kill their targets, T cell receptor signaling could initiate
trafficking changes that allow Hh signaling to
direct secretory lysosomes containing Smo to
the plasma membrane. How Smo relocation
leads to Gli activation, and if it is important for
MTOC polarization toward the immunological synapse, remains to be determined.
Do these data support the idea that the
immunological synapse is a frustrated cil-
ium? Hh signaling functions in Drosophila
melanogaster without cilia, so Hh signal-
ing does not necessarily require cilia (5).
And while the ability of the MTOC to inter-
act with the plasma membrane during secre-
tion is reminiscent of the basal body below
the cilia, basal bodies are anchored to the
plasma membrane by a specialized complex
of proteins. The MTOC of the cytotoxic T cell
appears to have a much more dynamic inter-
action with the plasma membrane, interact-
ing only transiently with it (3). If the func-
tion of primary cilia, however, is mainly to
sequester signaling components, this may
be achieved in T cells through a specialized
vesicular trafficking system. In this context,
the Hh pathway may control such traffick to
the membrane through MTOC translocation.
References
1. M. de la Roche et al., Science 342, 1247 (2013).
2. S. C. Goetz, K. V. Anderson, Nat. Rev. Genet. 11, 331
(2010).
3. J. C. Stinchcombe et al., Nature 443, 462 (2006).
4. F. Finetti et al., Nat. Cell Biol. 11, 1332 (2009).
5. J. Briscoe, P. P. Thérond, Nat. Rev. Mol. Cell Biol. 14, 418
(2013).
6. N. Sasaki et al., Mol. Cell. Neurosci. 45, 335 (2010).
7. A. H. Polizio et al., J. Biol. Chem. 286, 19589 (2011).
8. R. Teperino et al., Cell 151, 414 (2012).
Why did the plate boundary fault at the Japan Trench slip tens of meters to generate a devastating
tsunami in the Tohoku–Oki earthquake on 11
March 2011? Does the large slip in the shal-
low part of the fault represent a common pro-
cess in subduction zones, or does it reflect
site-specific geological conditions? Using the
scientific drilling vessel Chikyu and working
at the limit of drilling technology, research-
ers of the Japan Trench Fast Drilling Proj-
ect (JFAST) have retrieved rock samples and
made measurements in the culprit fault zone
to seek answers. Their findings are reported
in three papers in this issue. Based on differ-
ent types of observations, Chester et al. on
page 1208 (1), Fulton et al. on page 1214 (2),
and Ujiie et al. on page 1211 (3) show that an
important reason for the large slip is that the
shallow fault zone is thin and weak.
The Tohoku rupture started at a depth of
about 20 to 30 km and rapidly propagated in
all directions along the plate boundary fault
(referred to as the megathrust) to grow into
a magnitude 9 earthquake (see the figure).
According to various observations, the maximum slip exceeded 50 m near or at the trench.
The large shallow slip caused the sloping sea
floor above the megathrust to leap eastward,
and the sudden disturbance to the seawater
resulted in a huge tsunami.
Faults slip at a wide variety of rates.
Earthquake rupture, or seismic slip, is fault
slip at the highest rate. Traditionally, the
shallowest portion of a subduction mega-
1Pacific Geoscience Centre, Geological Survey of Canada,
Natural Resources Canada, Sidney, British Columbia, Canada V8L 4B2. 2Kochi Institute for Core Sample Research,
JAMSTEC, Nankoku, Kochi, 783-8502 Japan. E-mail: kelin.
wang@nrcan-rncan.gc.ca
10.1126/science.1248078