Biology Reference
In-Depth Information
Drosophila
inhibitor of apoptosis (IAP), and activate apoptosis (Challa
et al.
,
2007; Igaki
(2009a) addressed the
contribution of Drosophila HtrA2 to apoptosis induced by a variety of conditions,
including
et al.
, 2007; Khan
et al.
, 2008). Tain
et al.
-ray or UV irradiation, staurosporine exposure and developmentally
regulated cell death but surprisingly found no requirement for HtrA2 in these
mechanisms.
Overall, the reports indicate that
HtrA2
mutants have a markedly
weaker phenotype than
and suggest HtrA2 does not play a central role
in the major function(s) of PINK1 that are responsible for conferring
PINK1
PINK1
phenotypes. However, genetic interaction studies have the potential to reveal
less obvious functional relationships. A previous study had shown using over-
expression paradigms that
PINK1
and
HtrA2
may be functionally related
(Whitworth
et al.
, 2008). First, targeted overexpression of either
PINK1
or
under standard conditions (25
C) caused mild defects in eye morphology
or pigmentation; however, co-overexpression of both genes synergistically en-
hanced the phenotype, suggesting a cooperative function. This result was corro-
borated by Yun
HtrA2
et al.
(2008). Second,
PINK1
overexpression phenotype is
partially suppressed by loss of
HtrA2
, while conversely an
HtrA2
overexpression
phenotype is not suppressed by
, 2008),
suggesting that HtrA2 functions downstream of PINK1. In contrast, Yun
PINK1
mutations (Whitworth
et al.
et al.
were not able to detect suppression of the eye phenotypes in a similar manner;
however, these experiments were conducted at unusually high temperatures
(29
C) which is well known to confound analysis of eye morphology (Kramer
and Staveley, 2003), so perhaps the subtle effects reported by Whitworth
et al.
were missed. Complementary studies on loss-of-function phenotypes revealed
that
PINK1;HtrA2
double mutants do not show enhancement of
PINK1
mutants
alone, consistent with them acting in a common pathway (Tain
et al.
, 2009a;
Yun
et al.
, 2008). Furthermore, overexpression of
HtrA2
can partially substitute
for loss of
PINK1
(Tain
et al.
, 2009a), similar to the suppression of
PINK1
by
overexpression described above. Together, these findings are consistent
with HtrA2 acting in a common pathway downstream of PINK1, which
would support the previously reported molecular interactions (Plun-Favreau
et al.
parkin
, 2007).
But what about HtrA2's relationship to parkin? Interestingly, no genet-
ic interaction was detected between
using overexpression
paradigms, suggesting they may do not share a common function (Whitworth
et al.
HtrA2
and
parkin
double mutants display a
stronger locomotor phenotype than either mutant alone (Tain
, 2008). Tain
et al.
also reported that
parkin:HtrA2
, 2009a),
again supporting a view that HtrA2 acts in parallel pathway to parkin. Finally,
while loss of either
et al.
can partially suppress a PINK1 overexpres-
sion phenotype, attenuating both genes together is sufficient to completely
suppress the overexpression of PINK1 (Whitworth
HtrA2
or
parkin
et al.
, 2008). Taken together