Molecular Mechanisms in Exocytosis and Endocytosis
The Sla2p/HIP1/HIP1R family: similar structure,
similar function in endocytosis?
Irit Gottfried*, Marcelo Ehrlich†1 and Uri Ashery*1
*Department of Neurobiology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel and †Department of Cell Research and Immunology, Faculty
of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
Abstract
HIP1 (huntingtin interacting protein 1) has two close relatives: HIP1R (HIP1-related) and yeast Sla2p. All three
members of the family have a conserved domain structure, suggesting a common function. Over the past
decade, a number of studies have characterized these proteins using a combination of biochemical, imaging,
structural and genetic techniques. These studies provide valuable information on binding partners, structure
and dynamics of HIP1/HIP1R/Sla2p. In general, all suggest a role in CME (clathrin-mediated endocytosis) for
the three proteins, though some differences have emerged. In this mini-review we summarize the current
views on the roles of these proteins, while emphasizing the unique attributes of each family member.
Introduction
CME (clathrin-mediated endocytosis) is a well-studied
mechanism involved in many important cell functions, such
as the continuous uptake of essential nutrients [1,2], recycling
of synaptic vesicles [3], modulation of signal transduction
by controlling the levels of surface receptors and by serving
as a mechanism for signal compartmentalization [4,5].
The coordination of coated-pit assembly, cargo inclusion
and vesicle scission requires the dynamic interaction
of many proteins, one of which is HIP1 (huntingtininteracting protein 1). The mammalian HIP1 was identified
in 1997 as an interactor of huntingtin, a protein that
when mutated is involved in the genetic neurodegenerative
disorder Huntington’s disease [6,7]. The mutated huntingtin
has reduced affinity for HIP1, suggesting that the impaired
interaction could be part of the disease mechanism [7]. HIP1’s
yeast homologue, Sla2p, had been described a few years
earlier as a regulator of membrane cytoskeleton assembly [8],
and a third member of this family, HIP1R (HIP1-related),
was identified on the basis of structural homology [9,10].
Sla2p/HIP1/HIP1R structure and function
Common to the structure of all three Sla2p/HIP1/HIP1R
proteins is an N-terminally localized ANTH (AP180
N-terminal homology) domain, a central coiled-coil domain,
and a talin-like domain at the C-terminus [6,7,9] (Figure 1).
However, despite their structural similarity, experimental
evidence suggests functional diversity among these three
related proteins.
Key words: AP180 N-terminal homology (ANTH), endocytosis, huntingtin-interacting protein 1
(HIP1), HIP1-related (HIP1R), Sla2p, talin-like domain.
Abbreviations used: AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; ANTH,
AP180 N-terminal homology; CME, clathrin-mediated endocytosis; EGF, epidermal growth factor;
HIP1, huntingtin-interacting protein 1; HIP1R, HIP1-related; NMDA, N-methyl-d-aspartate; siRNA,
small interfering RNA.
1
Correspondence may be addressed to either of these authors (email marceloe@post.
tau.ac.il or [email protected]).
Biochem. Soc. Trans. (2010) 38, 187–191; doi:10.1042/BST0380187
The classical E/ANTH domains of epsin 1 and AP180
strongly bind PtdIns(4,5)P2 [11,12]. Moreover, this protein–
lipid interaction plays a determining role in their recruitment
to the membrane (the presumed site of action for endocytic
proteins). Similarly, the ANTH domain of Sla2p was found
to preferentially bind PtdIns(4,5)P2 [13]. However, deletion
of the ANTH domain did not prevent Sla2p’s localization
to cortical endocytic patches, suggesting its recruitment to
be dependent on additional protein–protein interactions
[13]. Though, despite being dispensable for recruitment, the
interaction of Sla2p’s ANTH domain with PtdIns(4,5)P2
was found to be required for the organization of actin at
the endocytic site [13]. Interestingly, the ANTH domains
of mammalian HIP1 and HIP1R do not preferentially bind
PtdIns(4,5)P2 , but PtdIns(3,4)P2 and PtdIns(3,5)P2 [14],
suggesting interactions with membranes that have different
lipid contents. This is puzzling as PtdIns(4,5)P2 is considered
to be an interaction hub in the clathrin interactome [15].
Furthermore, our unpublished results and others’ suggest
a high degree of co-localization of HIP1 and HIPR with
additional structural components of the clathrin-coated pit.
Thus, either there exists a diversity in lipid composition
in the immediate proximity of the coated pit or additional
molecular elements play a determining role in the recruitment
of HIP1 and HIP1R to the coated pit (discussed below).
The talin-like domain, also called the I/LWEQ module or
the THATCH domain [16], is an actin-binding domain found
in proteins that serve as linkers between the actin cytoskeleton and cellular compartments. The talin-like domains
of Sla2p and HIP1R have been shown to bind F-actin
(filamentous actin) [16–20], and indeed, several mutations
in these proteins caused disruption in actin binding or
organization [16,17,21,22]. In contrast, controversy exists
as to the actin-binding capabilities of the HIP1 talin-like
domain. While Legendre-Guillemin et al. [19] did not find
significant actin binding by HIP1 , Wilbur et al. [18] reported
actin binding that was approx. 7.5 times weaker than that of
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Figure 1 Schematic representation of the domain structure of
HIP1, HIP1R and Sla2p
Arrows point to the binding sites of some of their known interactors, as
indicated. In addition, the coiled-coil domain enables dimerization. AP2,
adaptor protein 2; CHC, clathrin heavy chain; CLC, clathrin light chain.
HIP1R, and Senetar et al. [20] found HIP1’s affinity to actin
to be very close to that of HIP1R. Notably, no disruption
of actin organization has so far been described on alteration
in the expression levels of HIP1. It is important to note that
the actin-binding capacity of HIP1 and HIP1R is regulated
by both intramolecular and intermolecular interactions. The
USH (upstream helix) domain, which is present in all three
proteins, inhibits actin binding by an intrasteric inhibitory
mechanism [20]. Moreover, the proline-rich domain, which
is present in HIP1R but not HIP1, mediates its binding to
the SH3 (Src homology 3) domain of cortactin, an interaction
which potentially determines its actin-modifying potential
and its function in CME [23].
The central domain of the Sla2p/HIP1/HIP1R proteins
contains a coiled-coil domain and several consensus
sequences enabling protein–protein interactions. Binding experiments have shown that all three proteins interact with the
clathrin light chain [19,24–26]. This binding is of functional
importance as it may modulate not only recruitment to the
clathrin-coated pit/vesicle, but also the ability of HIP1 and
HIP1R to bind to actin [18]. Furthermore, even though
reduced affinity to actin on clathrin binding is common to
both HIP1 and HIP1R, the extent of this phenomenon is
substantially larger in the case of HIP1R [18], a fact that
may be of importance in the context of a coated pit, where
all three factors (clathrin light chain, HIP1 and HIP1R) are
thought to be present. HIP1’s central domain has been shown
to have several additional partners, such as clathrin heavy
chain, AP2 (adaptor protein 2), and huntingtin [6,19,27–29]
(Figure 1). Interactions of HIP1 have also been detected with
androgen receptor, EGF (epidermal growth factor) receptor
and NMDA (N-methyl-D-aspartate) receptor [30–32]. In this
context, HIP1 may function as a cargo-specific endocytic
adaptor. Sla2p’s central domain was found to additionally
bind Sla1p, another regulator of actin organization [33].
Another interaction attributed to the central domain is the
homo/heterodimerization of the proteins. While there seems
to be agreement on their homodimerization [18,22], the
heterodimerization reported by Legendre-Guillemin et al.
[19] was recently apparently contradicted by the findings
of Wilbur [18] that a mixture of the coiled-coil domains of
HIP1 and HIP1R results in strong homodimerization of each
protein, with no significant heterodimerization.
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Authors Journal compilation The effects of Sla2p/HIP1/HIP1R
silencing
The roles of the endogenous proteins were investigated using
deletion mutants and silencing techniques. However, these
studies yielded conflicting results: several HIP1-deficient
mice created over the years unexpectedly exhibited different
phenotypes. Rao et al. [34] were the first to create mice with
targeted deletion of murine Hip1. These mice were viable
and developed normally, except for testicular degeneration
with increased apoptosis of post-meiotic spermatids found
in the adult male mice. Another mouse, created by Metzler
et al. [35], displayed a more severe phenotype: from the age
of 12 weeks the mice developed growth retardation, tremor,
thoracolumbar kyphosis and a reproductive defect. The phenotype was progressive and resulted in premature death several
months after development of the kyphosis. Additionally,
those authors showed that cultured neurons from these mice
are less susceptible to NMDA-induced excitotoxicity, and
that long-term depression measurements from hippocampal
slices show a slight reduction for Hip1-deficient mice compared with wild-type mice [30]. It is worth noting that brain
morphology, cortical, hippocampal and striatal volumes, and
densities of hippocampal and striatal neurons were indistinguishable from those of wild-type mice [35]. Additional
mice were created by Oravecz-Wilson et al. [36]. Aside from
the previously described spinal defect, these mice displayed
haematopoietic abnormalities, micro-ophthalmia and cataracts [36]. Possible explanations for the phenotype discrepancies are the possible creation of hypomorphic alleles, differences in mouse strains, and neighbouring gene effects [36].
Symptoms specific to the endocytic pathway were
described in the mice created by Metzler et al. [35]. At the
cellular level, internalization of AMPA (α-amino-3-hydroxy5-methylisoxazole-4-propionic acid) receptors following
stimulation was impaired in cortical neurons derived from
Hip1-knockout mice, while surprisingly, transferrin-receptor
internalization remained intact in these cells [35]. These
results suggest a role for HIP1 in only specific forms of
endocytosis, i.e. AMPA-receptor internalization. However,
other studies showed that transferrin uptake is inhibited in
cells expressing a fragment of HIP1 [27], and thus the question
of HIP1’s functional specificity in endocytosis remains open.
In neurons, HIP1 was shown to be localized to dendritic
structures and to affect AMPA receptor trafficking [35]. A
morphological study using immunogold labelling confirmed
that HIP1 is localized predominantly post synaptically
but also demonstrated that some HIP1 labelling is found
at presynaptic terminals [37]. Further examination of
synaptic transmission in Hip1−/− mice reported a small
but significant increase in paired-pulse facilitation and
reduced recovery from synaptic depression [38]. In addition,
the Caenorhabditis elegans HIP1 homologue (hipr-1) was
suggested to be involved in presynaptic activity [38]. These
findings suggest that HIP1 affects presynaptic function, but
further studies are needed to examine if these effects relate to
alterations in endocytosis or to other processes.
Molecular Mechanisms in Exocytosis and Endocytosis
Figure 2 Suggested roles for Sla2p, HIP1 and HIP1R in the initial steps of endocytosis
(A) Sla2p arrives at the pre-existing coated pit in the cell cortex, recruits actin-remodelling proteins and dissociates in parallel
to clathrin. (B) HIP1R arrives at the pit in parallel to clathrin, and probably participates in clathrin assembly; it interacts
sequentially with actin-remodelling proteins and then dissociates in parallel to clathrin. HIP1 dynamics have not yet been
characterized. Similar to HIP1R, it is capable of clathrin assembly (in vitro), so it probably arrives in parallel to clathrin; its
actin-binding capabilities are controversial and it has not yet been shown to have an effect on actin structure, so it may
dissociate earlier than has been proposed for HIP1R and Sla2p, or in parallel to clathrin as shown for the other two proteins.
Questions remain as to HIP1’s time of arrival, its interaction with actin and the actin-remodelling proteins, and the timing of
its dissociation (indicated by question marks).
Deletion of Hip1r in mice caused no noticeable phenotype.
Hip1r homozygous mutant mice were viable and fertile
without obvious morphological abnormalities [39]. However,
double-knockout of both HIP1 and HIP1R aggravated the
phenotype of the Hip1-deficient mice [39]. Surprisingly, no
abnormalities were found in endocytosis, PtdIns 3-kinase
signalling or actin dynamics in any of the examined cell
types [MEFs (mouse embryonic fibroblasts), spleen cells]
[40]. In contrast, reducing HIP1R levels using siRNA
(small interfering RNA) altered endocytosis and caused
abnormal cytoskeletal actin organization [41]. In particular,
clathrin-coated structures and their endocytic cargo became
stably associated with dynamin, actin, and the Arp2/3
(actin-related protein 2/3) actin-remodelling complex [41].
In yeast, cells lacking Sla2p have severe defects in
actin organization, cell morphology, and endocytosis.
Interestingly, the early endocytic factors are recruited and
form cortical patches, but these do not internalize. In
addition, actin comet tails are formed at these sites and grow
into the cytosol [8,22,42].
Therefore, although these experiments suggest a role in
endocytosis, it is not clear why in some cases the different
deletion methods do not affect endocytosis, thus a clear
classification of the proteins’ functions is prevented. This
apparent discrepancy may stem from the timeline of the
imbalance of expression levels (between HIP1/HIP1R and
its interactors), which differs between the two methods,
and may allow for a different compensatory response.
Suggested modes of action
Based on their domain structure, binding partners,
knockdowns and other experimental evidence, several models
for Sla2p/HIP1/HIP1R function have been proposed.
The most conclusive results were found for yeast Sla2p:
dynamic characterization of Sla2p shows that it arrives at
existing endocytic patches with a ∼25-s delay relative to
clathrin and dissociates simultaneously with clathrin upon
recruitment of actin-related proteins [26,42]; in addition,
Sla2p cells show normal recruitment of the early endocytic
machinery but no internalization, and creation of abnormal
actin structures [8,22,42]. These results strongly support the
notion that Sla2p serves as a bridge, connecting the endocytic
patch to the cortical actin cytoskeleton [25] (Figure 2A).
For HIP1 and HIP1R, the picture is not as clear. It
has been suggested that these proteins act as heterodimers
and, similar to Sla2p, can connect the coated pit to actin
structures [43–45]. This was further supported by the effects
of Hip1r siRNA, which were quite similar to those of Sla2p
knockouts [41]. However, in light of the new evidence for the
unlikelihood of these proteins’ heterodimerization [18], this
model of their function becomes less feasible. In addition,
the different phenotypes of the knockout mice also imply
functional differences for the two mammalian proteins.
A more likely notion is that HIP1 and HIP1R perform
partially overlapping functions, as their combined knockout
produces a more severe phenotype [39], and re-expression of
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HIP1 alone is enough to ameliorate many of the symptoms
[40].
It is very possible that HIP1R, like Sla2p, has a role in actin
regulation during endocytosis, as inferred from its silencing
experiments [23,41]. Yet, due to the potentially different roles
played by actin in endocytosis in yeast and mammals, HIP1R
might have an additional, earlier role. In support of this notion
is the arrival of Sla2p to pre-existing clathrin patches, which
contrasts with the parallel dynamics of HIP1R and clathrin
[24] (Figure 2B). Furthermore, both HIP1 and HIP1R are
endowed with the capacity to promote clathrin assembly
in vitro [19,24]. Moreover, actin polymerization may also play
distinct roles at different steps of the endocytic event in mammalian cells [46,47]. Apart from its endocytic role, recent results associate HIP1R to the apoptotic pathway, through interaction with a member of the Bcl-2 pro-apoptotic family [48].
The function of HIP1 is even less clear. Unlike the other
two members of this family, no effect on actin organization
has so far been reported for HIP1. In addition, the time
frame of HIP1 recruitment and dissociation from coated
pits/vesicles is currently unknown (Figure 2B, question
marks). Nonetheless, different reports have suggested that
HIP1 functions in different stages of endocytosis: from the
very early recruitment of clathrin coat components [29],
through the internalization of the coated pit/vesicle [35] and
later, in the transition from early to late endosomes [14]. Apart
from endocytosis, HIP1 has also been associated with other
cellular processes such as tumorigenesis [49], transcription
regulation [32] and cell death [50,51]. The association of HIP1
with the EGF receptor and its proposed role in tumorigenesis
[31,49] is of particular interest: as internalization is considered
to be a mechanism of receptor down-regulation; this is
in apparent contrast to a proposed role for HIP1 as a
cargo-specific endocytic adaptor. Importantly, HIP1 has been
described to interact with a broad spectrum of factors in different intracellular compartments [6,19,27–32,51]. This and
the divergent consequences of alterations in HIP1 expression
levels support the notion that HIP1 functions at several points
along the clathrin-endocytic pathway, in addition to clathrinindependent regulation of cellular processes. Of particular interest is the nuclear localization of HIP1, due to the presence
of a C-terminally localized nuclear localization signal [32].
In this sense, HIP1 is an additional member of the group of
endocytic proteins that perform nucleocytoplasmic shuttling
[52]. Taken together, these considerations raise the need for
further quantitative measurements of the dynamic parameters
of HIP1 localization, under different cellular conditions, to
unravel the relevant stages of endocytosis in which HIP1
participates, and the full extent of its functional capacities.
Concluding remarks
Despite their structural similarity, the members of the
Sla2p/HIP1/HIP1R family probably perform unique functions. In light of this potential functional diversity, the tendency to minimize their uniqueness and accentuate a presumed
redundancy should be avoided. Despite extensive research
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Authors Journal compilation over the years there is a need for further experimentation,
especially using high-resolution techniques, to unravel the
steps of these proteins’ functions. Better characterization of
both their common and unique functions will provide us with
a better understanding of key processes in the cell.
Since submission of the present paper, we have published
our findings that HIP1 shares similar dynamics to those of
clathrin in coated pits and functions in the last steps of coated
pit maturation and the formation of coated vesides [53].
Funding
This study was supported by grants from the Israel Science
Foundation [grant number 1211/07 (to U.A.)], and The Clore
Foundation Scholars Programme (to I.G.).
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Received 3 April 2009
doi:10.1042/BST0380187
C The
C 2010 Biochemical Society
Authors Journal compilation 191