About

Enfu Hui, PhD, is a Principal Investigator and Professor in the Department of Biological Sciences at the University of California, San Diego. He is a researcher, educator, and mentor specializing in biochemistry and immunology. His professional role involves leading the Hui Lab, where he oversees a team of postdoctoral fellows, graduate students, and undergraduate researchers. The lab focuses on advancing scientific understanding in the fields of cell and developmental biology, with a particular emphasis on biochemical and immunological research.

Research topics

• Immunology
• Biology
• Cell biology
• Cancer research
• Biochemistry
• Chemistry

Selected publications

• PD1-induced Shp2 condensation organizes inhibitory signalosomes through selective substrate partitioning

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-11

  articleOpen accessSenior authorCorresponding

  The formation of microclusters is a hallmark of PD1 engagement with its ligands, yet the physical basis and functional significance of this phenomenon remain unclear. Here we show that ligand-bound PD1 licenses Shp2 self-association and liquid-liquid phase separation (LLPS), producing dynamic PD1:Shp2 condensates whose liquidity depends on Shp2 catalytic activity. Mutations that selectively disrupt Shp2 self-association weaken PD1 microcluster formation and impair PD1 inhibitory function. Mechanistically, PD1-induced Shp2 LLPS promotes the co-compartmentalization of signaling substrates such as CD3ζ and CD28, thereby facilitating its dephosphorylation. These findings identify Shp2 LLPS as an intrinsic organizing principle of the PD1 inhibitory pathway that links enzymatic activation, substrate selectivity and mesoscale assembly to suppress T cell activation.

  PublisherOA PDFDOI

• Abstract 6538: A phase-separation mechanism underlying PD-1-mediated T-cell inhibition via Shp2 condensation

  Cancer Research · 2026-04-03

  articleSenior author

  Abstract Microcluster formation is a hallmark of PD1 engagement, but its physical basis and functional impact have remained unclear. We show that ligand-bound PD1 triggers Shp2 self-association and liquid liquid phase separation, generating dynamic condensates whose liquidity depends on Shp2 catalytic activity. Mutations that disrupt Shp2 self-association weaken PD1 microclusters and reduce inhibitory signaling. These findings identify Shp2 phase separation as a fundamental organizing mechanism of the PD1 pathway, linking enzymatic activation, substrate selectivity, and higher-order assembly to suppress T cell responses. This work reveals a biophysical mechanism of PD1-mediated immune regulation with implications for improving checkpoint blockade therapies. Citation Format: Takeya Masubuchi, George Wen, Xiaoxian Song, Haian Shao, Enfu Hui. A phase-separation mechanism underlying PD-1-mediated T-cell inhibition via Shp2 condensation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6538.

  PublisherDOI

• Orientation-dependent CD45 inhibition with viral and engineered ligands 2152

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this complex and found that the E3/49K protein is composed of three immunoglobulin domains assembled as”beads on a string” that compel CD45 into a closely abutted dimer by cross-linking the CD45 D3 domain, leading to steric inhibition of its intracellular phosphatase activity. Inspired by the E3/49K mechanism, we engineered CD45 surrogate ligands that can fine-tune T cell activation by dimerizing CD45 into different orientations and proximities. The adenovirus E3/49K protein has taught us that, despite a lack of a known ligand, CD45 activity can be modulated by extracellular dimerizing ligands that perturb its phosphatase activity and alter T cell responses. Funding Sources This work was supported by NCI R01 CA177684 (K.C.G.); Howard Hughes Medical Institute (K.C.G.); Ludwig Institute for Cancer Research (K.C.G.); NCI, R37 CA239072 (E.H.); NIH, DP2 CA272092(R.G.M.); and CRI Lloyd J. Old STAR, CRI4960 (R.G.M.). Topic Categories Viral Immunology (VIR)

  PublisherOA PDFDOI

• Themis dominates T cell exhaustion by regulation of TCR and PD-1 signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-19 · 2 citations

  preprintCorresponding

  Abstract T cell exhaustion is important to protect the host from immunopathology during chronic viral infection, but it also impairs T cell anti-tumor immunity 1–5 . A fundamental unresolved question is whether and how T cell exhaustion is determined at the onset of TCR signaling 6–8 . Here we report an unexpected role of Themis, a TCR-proximal signaling molecule 9 , in T cell exhaustion. Chronic viral infection in mice usually leads to T cell exhaustion and survival of the host. Surprisingly, Themis T-cell conditional knockout mice died from severe CD8 + -dependent lung immunopathology in chronic viral infection, showing Themis’ importance in establishing T cell exhaustion. We found that Themis-deficient CD8 + T cells were hyperactivated at the single-cell level - producing more TNF and IFNγ compared to wild-type counterparts - but defective in population-level expansion. Moreover, TCF-1 and TOX expression were inhibited in Themis-deficient CD8 + T cells, thereby impairing differentiation of exhausted T cell precursors (T-pex) and maintenance of terminally exhausted T cells (T-ex), respectively. Mechanistically, Themis initially promotes TCR signaling to induce PD-1 expression and subsequently mediates PD-1 signaling. In the latter, Themis binds to PD-1 and promotes PD-1 phosphorylation and its recruitment of SHP2, thereby acting as a negative regulator to inhibit T cell effector functions. Without Themis, the orderly regulation of TCR and PD-1 signaling, and therefore exhaustion, is disrupted. Thus, our results unequivocally demonstrate that Themis-mediated early TCR signaling plays a decisive role in T cell exhaustion and provide a novel mechanism of PD-1 signaling through Themis.

  PublisherDOI

• BPS2025 - Differential biophysical and functional properties of human vs. mouse PD1

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

• Obesity rewires CD8+ T cell iron metabolism in adipose tissue to fuel metabolic inflammation

  Metabolism · 2025-11-17 · 1 citations

  article
  PublisherDOI

• Human PD1 verus mouse PD1 - how different are they? 3290

  The Journal of Immunology · 2025-11-01

  articleOpen access1st authorCorresponding

  Abstract Description Mechanistic understanding of the inhibitory immunoreceptor PD1 is largely based on mouse models, but human and mouse PD1 orthologs exhibit only 59.6% identity in amino acid sequences. We show that human PD1 is more inhibitory than mouse PD1 due to stronger interactions with the ligands PDL1 and PDL2 and with the effector phosphatase Shp2. A novel motif highly conserved among PD1 orthologs in vertebrates except in rodents is primarily responsible for the differential Shp2 recruitment. Evolutionary analysis suggested that rodent PD1 orthologs uniquely underwent functional relaxation, particularly during the K-Pg boundary. Humanization of the PD1 intracellular domain disrupted the anti-tumor activity of mouse T cells while increasing the magnitude of anti-PD1 response. Together, our study uncovers species-specific features of the PD1 pathway, with implications to PD1 evolution and differential anti-PD(L)1 responses in mouse models and human patients. Funding Sources Supported by R37 CA239072 from the National Institute of Health, the Hartwell Foundation, Human Frontiers Science Program and JST PRESTO grant (JPMJPR22EB) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

  PublisherOA PDFDOI

• The inhibitory receptor Siglec-E controls antigen-presenting cell activation and T cell–mediated transplant rejection

  Science Translational Medicine · 2025-05-07 · 7 citations

  articleOpen access

  After transplantation, inflammation and tissue injury release danger signals that activate myeloid cells, driving adaptive immune responses and acute rejection. Current immunosuppressants primarily target T cells but inadequately control innate immunity. Regulatory signals controlling innate responses in transplantation remain elusive. The sialic acid-binding immunoglobulin-like lectin-E (Siglec-E, or SigE) binds sialylated ligands to suppress inflammation. In mouse heart transplants, SigE is up-regulated in graft-infiltrating myeloid cells, including dendritic cells (DCs). SigE deficiency in recipients, but not donors, accelerates acute rejection by enhancing DC activation, nuclear factor κB (NF-κB) signaling, and tumor necrosis factor-α (TNF-α) production, thereby boosting alloreactive T cell responses. Conversely, SigE overexpression on DCs reduces activation by danger signals and their T cell allostimulatory capacity. The human homologs Siglecs-7 and -9 were up-regulated in rejecting allograft biopsies, and their higher expression correlated with improved allograft survival. Thus, SigE/7/9 is a crucial inhibitory receptor controlling antigen-presenting cell activation and T cell-mediated transplant rejection, offering therapeutic potential.

  PublisherOA PDFDOI

• Functional differences between rodent and human PD-1 linked to evolutionary divergence

  Science Immunology · 2025-01-03 · 29 citations

  articleOpen accessSenior authorCorresponding

  Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and mouse PD-1 share only 59.6% amino acid identity. Here, we found that human PD-1 is more inhibitory than mouse PD-1, owing to stronger interactions with the ligands PD-L1 and PD-L2 and more efficient recruitment of the effector phosphatase Shp2. In a mouse melanoma model with adoptively transferred T cells, humanization of a PD-1 intracellular domain disrupted the antitumor activity of CD8 + T cells and increased the magnitude of anti–PD-1 response. We identified a motif highly conserved across vertebrate PD-1 orthologs, absent in rodents, as a key determinant for differential Shp2 recruitment. Evolutionary analysis suggested that PD-1 underwent a rodent lineage–specific functional attenuation during evolution. Together, our study uncovers species-specific features of the PD-1 pathway, with implications for PD-1 evolution and differential anti–PD-(L)1 responses in mouse models and human patients.

  PublisherOA PDFDOI

• Concentration-dependent antibody specificity profiles of human leukocyte DQ antigens and predictions of functional epitopes

  Human Immunology · 2024-09-01

  article
  PublisherDOI

Recent grants

• Regulation of PD-L1/PD-1 immune checkpoints by cis-interactions

  NIH · $2.5M · 2019–2026

Frequent coauthors

• Edwin R. Chapman

  Howard Hughes Medical Institute

  44 shared

• Ronald D. Vale

  Janelia Research Campus

  29 shared

• Xiaolei Su

  Yale Cancer Center

  26 shared

• Jihong Bai

  Fred Hutch Cancer Center

  12 shared

• Yunlong Zhao

  East China Normal University

  12 shared

• Jonathon A. Ditlev

  University of Toronto

  11 shared

• Michael K. Rosen

  Howard Hughes Medical Institute

  11 shared

• Xiaozheng Xu

  Zhejiang A & F University

  10 shared

Labs

• Hui LabPI

Education

• Ph.D., Physiology

  University of Wisconsin Madison

  2009

• Bachelor of Science, Biology

  Tsinghua University

  2003

Awards & honors

• Searle Scholar Award
• Pew Scholar Award
• American Cancer Society Research Scholar Award
• NCI R37 MERIT Award for early-stage investigators
• Department of Defense Melanoma Research Program Team Science…