Enfu Hui

Enfu Hui
University of California, San Diego | UCSD · Division of Biological Sciences

Doctor of Philosophy
Associate Professor at UCSD Research on T cell signaling

About

48
Publications
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3,181
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Publications

Publications (48)
Article
Reconstituting functional transmembrane (TM) proteins into model membranes is challenging due to the difficulty of expressing hydrophobic TM domains, which often require stabilizing detergents that can perturb protein structure and function. Recent model systems solve this problem by linking the soluble domains of membrane proteins to lipids, using...
Article
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Dual blockade of the PD-1 and TIGIT coinhibitory receptors on T cells shows promising early results in cancer patients. Here, we studied the mechanisms whereby PD-1 and/or TIGIT blockade modulate anti-tumor CD8⁺ T cells. Although PD-1 and TIGIT are thought to regulate different costimulatory receptors (CD28 and CD226), effectiveness of PD-1 or TIGI...
Article
Full-text available
A large number of inhibitory receptors recruit SHP1 and/or SHP2, tandem-SH2-containing phosphatases, through phosphotyrosine-based motifs ITIM and ITSM. Despite the similarity, these receptors exhibit differential effector binding specificities, as exemplified by the immune checkpoint receptors PD-1 and BTLA, which preferentially recruit SHP2 and S...
Preprint
Cellular transmembrane (TM) proteins are essential sentries of the cell facilitating cell-cell communication, internal signaling, and solute transport. Reconstituting functional TM proteins into model membranes remains a challenge due to the difficulty of expressing hydrophobic TM domains and the required use of detergents. Herein, we use a intein-...
Preprint
Full-text available
Numerous inhibitory immunoreceptors operate by recruiting phosphatase effectors Shp1 and Shp2 through conserved motifs ITIM and ITSM. Despite the similarity, these receptors exhibit distinct effector binding specificities, as exemplified by PD-1 and BTLA, which preferentially recruit Shp2 and Shp1 respectively. The molecular basis of Shp1/Shp2 disc...
Article
A T cell receptor (TCR) mediates antigen-induced signaling through its associated CD3ε, δ, γ, and ζ, but the contributions of different CD3 chains remain elusive. Using quantitative mass spectrometry, we simultaneously quantitated the phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of all CD3 chains upon TCR stimulation...
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Blockade antibodies of the immunoinhibitory receptor PD-1 can stimulate the anti-tumor activity of T cells, but clinical benefit is limited to a fraction of patients. Evidence suggests that BTLA, a receptor structurally related to PD-1, may contribute to resistance to PD-1 targeted therapy, but how BTLA and PD-1 differ in their mechanisms is debate...
Article
Combined immunotherapy targeting the immune checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), or CTLA-4 and the PD-1 ligand (PD-L1) exhibits superior anti-tumor responses compared with single-agent therapy. Here, we examined the molecular basis for this synergy. Using reconstitution assays...
Article
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A major unanswered question is how a TCR discriminates between foreign and self-peptides presented on the APC surface. Here, we used in situ fluorescence resonance energy transfer (FRET) to measure the distances of single TCR–pMHC bonds and the conformations of individual TCR–CD3ζ receptors at the membranes of live primary T cells. We found that a...
Article
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T cells are central players of our immune system, as their functions range from killing tumorous and virus‐infected cells to orchestrating the entire immune response. In order for T cells to divide and execute their functions, they must be activated by antigen‐presenting cells (APCs) through a cell‐cell junction. Extracellular interactions between...
Preprint
T cell-mediated destruction of tumors and virus-infected cells is restricted by co-inhibitory receptors such as programmed cell death protein 1 (PD-1). Monoclonal antibodies blocking PD-1 have produced impressive clinical activity against some human cancers, but durable response is limited to a minority of patients. Previous results suggest that B...
Preprint
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Combined immunotherapy with anti-PD-1/PD-L1 and anti-CTLA4 has resulted in superior clinical responses compared to single agent therapy. The underlying mechanisms for this synergy have yet to be elucidated and investigations have largely focused on cellular interactions. Herein, we report a molecular crosstalk in which the PD-1 ligand PD-L1 and the...
Article
Full-text available
Hui details the cell biology underlying the action of immune checkpoint inhibitors.
Conference Paper
p>Immunotherapy, which harnesses the immune system to combat cancers, is a paradigm-shifting approach in oncology. One important branch of immunotherapy is to use drugs to perturb molecular interactions at the T-cell–antigen presenting cell (APC) interface. In particular, antibodies that block the T-cell coinhibitory receptor PD-1 or its ligand PD-...
Preprint
Full-text available
T-cell receptors (TCRs) detect specifically and sensitively a small number of agonist peptide-major histocompatibility complexes (pMHCs) from an ocean of structurally similar self-pMHCs to trigger antigen-specific adaptive immune responses. Despite intense efforts, the mechanism underlying TCR ligand discrimination remains a major unanswered questi...
Article
Full-text available
The PD-1 pathway, consisting of the co-inhibitory receptor PD-1 on T cells and its ligand (PD-L1) on antigen-presenting cells (APCs), is a major mechanism of tumor immune evasion. PD-1 and PD-L1 blockade antibodies have produced remarkable clinical activities against a subset of cancers. Binding between T cell-intrinsic PD-1 and APC-intrinsic PD-L1...
Article
Full-text available
T cell signaling initiates upon the binding of peptide-loaded MHC (pMHC) on an antigen-presenting cell to the T cell receptor (TCR) on a T cell. TCR phosphorylation in response to pMHC binding is accompanied by segregation of the transmembrane phosphatase CD45 away from TCR-pMHC complexes. The kinetic segregation hypothesis proposes that CD45 exclu...
Preprint
Full-text available
T cell signaling initiates upon binding of peptide-major histocompatibility complex (pMHC) on an antigen-presenting cell (APC) to the T cell receptor (TCR) on a T cell. TCR phosphorylation in response to pMHC binding is accompanied by segregation of the transmembrane phosphatase CD45 away from TCR-pMHC complexes. The kinetic segregation hypothesis...
Article
Full-text available
Programmed death-1 (PD-1) is a co-inhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). Here, by titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-re...
Preprint
Programmed death-1 (PD-1) is a co-inhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). Here, by titrating the strength of PD-1 signaling in both biochemical reconstitution systems and in T c...
Article
Activation of many cell surface receptors triggers the reorganization of downstream signaling molecules into micron- or submicron-sized clusters. However, the functional consequences of such clustering have been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activati...
Article
Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micron- or submicron-sized clusters. However, the functional consequences of such clustering has been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activa...
Article
Signaling through the T cell receptor (TCR) mediates T cell activation, differentiation, and proliferation. Previous microscopy studies have shown the spatial reorganization of signaling molecules into microclusters on the plasma membrane after TCR activation. However, how microclusters form and what roles these structures play in signal transducti...
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Full-text available
Ca(2+)-triggered release of neurotransmitters and hormones depends on soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) to drive the fusion of the vesicle and plasma membranes. The formation of the SNARE complex by the vesicle SNARE synaptobrevin 2 (syb2) and the two plasma membrane SNAREs syntaxin (syx) and SNAP-25 dr...
Article
T-cell receptor (TCR) phosphorylation is controlled by a complex network that includes Lck, a Src family kinase (SFK), the tyrosine phosphatase CD45 and the Lck-inhibitory kinase Csk. How these competing phosphorylation and dephosphorylation reactions are modulated to produce T-cell triggering is not fully understood. Here we reconstituted this sig...
Article
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Synaptotagmin-1 is a Ca(2+) sensor that triggers synchronous neurotransmitter release. The first documented biochemical property of synaptotagmin-1 was its ability to aggregate membranes in response to Ca(2+). However, the mechanism and function of this process were poorly understood. Here we show that synaptotagmin-1-mediated vesicle aggregation i...
Article
Full-text available
Synaptotagmin (syt) serves as a Ca(2+) sensor in the release of neurotransmitters and hormones. This function depends on the ability of syt to interact with other molecules. Syt binds to phosphatidylserine (PS)-containing lipid bilayers as well as to soluble N-ethylmaleimide sensitive factor receptors (SNAREs) and promotes SNARE assembly. All these...
Article
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The synaptic vesicle protein synaptotagmin I (Syt I) binds phosphatidylserine (PS) in a Ca(2+)-dependent manner. This interaction is thought to play a role in exocytosis, but its precise functions remain unclear. To determine potential roles for Syt I-PS binding, we varied the PS content in PC12 cells and liposomes and studied the effects on the ki...
Article
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Decades ago it was proposed that exocytosis involves invagination of the target membrane, resulting in a highly localized site of contact between the bilayers destined to fuse. The vesicle protein synaptotagmin-I (syt) bends membranes in response to Ca(2+), but whether this drives localized invagination of the target membrane to accelerate fusion h...
Article
Full-text available
Synaptotagmin (syt) 1 is localized to synaptic vesicles, binds Ca2+, and regulates neuronal exocytosis. Syt 1 harbors two Ca2+-binding motifs referred to as C2A and C2B. In this study we examine the function of the isolated C2 domains of Syt 1 using a reconstituted, SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor)-mediated, fus...
Article
Full-text available
Neuronal communication is mediated by Ca(2+)-triggered fusion of transmitter-filled synaptic vesicles with the presynaptic plasma membrane. Synaptotagmin I functions as a Ca(2+) sensor that regulates exocytosis, whereas soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) proteins in the vesicle and target membrane a...
Article
Full-text available
Synaptotagmin I is the Ca(2+) sensor for fast, synchronous release of neurotransmitter; however, the molecular interactions that couple Ca(2+) binding to membrane fusion remain unclear. The structure of synaptotagmin is dominated by two C(2) domains that interact with negatively charged membranes after binding Ca(2+). In vitro work has implicated a...
Data
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Note: Supplementary information is available on the Nature Structural & Molecular Biology website.
Article
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Synaptotagmin I (syt), an integral protein of the synaptic vesicle membrane, is believed to act as a Ca2+ sensor for neuronal exocytosis. Syt's cytoplasmic domain consists largely of two C2 domains, C2A and C2B. In response to Ca2+ binding, the C2 domains interact with membranes, becoming partially embedded in the lipid bilayer. We have imaged syt...
Article
Czibener et al. 2006. J. Cell Biol. doi:10.1083/jcb.200605004 [OpenUrl][1][Abstract/FREE Full Text][2] [1]: {openurl}?query=rft_id%253Dinfo%253Adoi%252F10.1083%252Fjcb.200605004%26rft_id%253Dinfo%253Apmid%252F16982801%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%
Article
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Synaptotagmin (Syt) VII is a ubiquitously expressed member of the Syt family of Ca2+ sensors. It is present on lysosomes in several cell types, where it regulates Ca2+-dependent exocytosis. Because [Ca2+]i and exocytosis have been associated with phagocytosis, we investigated the phagocytic ability of macrophages from Syt VII-/- mice. Syt VII-/- ma...
Article
Full-text available
Synaptotagmin I (syt), a transmembrane protein localized to secretory vesicles, functions as a Ca2+ sensor that facilitates SNARE-mediated membrane fusion. The cytoplasmic domain of syt harbors two C2-domains designated C2A and C2B. Upon binding Ca2+, C2A and C2B partially penetrate into membranes that contain anionic phospholipids. However, it is...
Article
Full-text available
Synaptotagmins (syts) are a family of membrane proteins present on a variety of intracellular organelles. In vertebrates, 16 isoforms of syt have been identified. The most abundant isoform, syt I, appears to function as a Ca²⁺ sensor that triggers the rapid exocytosis of synaptic vesicles from neurons. The functions of the remaining syt isoforms ar...
Article
Full-text available
The C2 domain originally referred to the second of four constant structural motifs in protein kinase C (PKC). Now this domain represents a large structural family sharing a homologous dimensional structure in many proteins that play important roles in many organisms. The C2A domain is one of the two C2 domains of synaptotagmin I involved in the Ca2...

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