Two CTLA-4 ligands, separate pHates

Humphries, Preston A.; Lo, Wan‐Lin

doi:10.1038/s41590-022-01296-x

Cited by 3 publications

(1 citation statement)

References 12 publications

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“…CTLA‐4 contains a YVKM internalization motif in the cytoplasmic region that interacts with the clathrin adaptor AP‐2, resulting in rapid endocytosis of CTLA‐4 from the cell surface. After the dissociation of AP‐2 and CTLA‐4, LRBA binds to the YVKM motif at the early endosome, allowing CTLA‐4 to enter the Rab11‐positive recycling endosome (Humphries & Lo, 2022; Janman et al., 2021; Rowshanravan et al., 2018). LRBA deletion inhibits CTLA‐4 translocation from the early endosome to the recycling endosome, resulting in CTLA‐4 lysosomal degradation (Janman et al., 2021).…”

Section: Discussionmentioning

confidence: 99%

LRBA signalosomes activate vasopressin‐induced AQP2 trafficking at recycling endosomes

Yanagawa,

Hara,

Ando

et al. 2023

The Journal of Physiology

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Aquaporin‐2 (AQP2) water channels are proteins that are recycled between intracellular vesicles and the apical plasma membrane in renal collecting ducts. Lipopolysaccharide‐responsive beige‐like anchor protein (LRBA) is a protein kinase A (PKA) anchoring protein that creates compartmentalized PKA signalling responsible for AQP2 phosphorylation. In response to increased plasma osmolality, vasopressin/cyclic adenosine monophosphate (cAMP)/PKA signalling phosphorylates AQP2, promoting AQP2 trafficking into the apical plasma membrane and increasing water reabsorption from urine. However, the molecular mechanisms by which LRBA mediates vasopressin‐induced AQP2 phosphorylation remain unknown. To investigate AQP2 intracellular localization and phosphorylation status in vivo, a density gradient ultracentrifugation technique was combined with an in situ proximity ligation assay, super‐resolution structured illumination microscopy and immunoelectron microscopy. Most of the AQP2 was localized on the recycling endosome in the presence of tolvaptan, a vasopressin type 2 receptor (V2R) antagonist. Desmopressin, a V2R agonist, phosphorylated AQP2, translocating it from the recycling endosome to the apical plasma membrane. In contrast, LRBA was constitutively localized at the recycling endosome. Therefore, LRBA and AQP2 were well colocalized in the absence of vasopressin stimulation. The loss of LRBA/PKA signalling by Lrba knockout impaired vasopressin‐induced AQP2 phosphorylation, resulting in AQP2 retention at the recycling endosome. Defective AQP2 trafficking caused low urinary concentrating ability in Lrba−/− mice. The LRBA‐PKA complex created compartmentalized PKA signalling at the recycling endosome, which facilitated AQP2 phosphorylation in response to vasopressin. imageKey points Membrane proteins are continuously internalized into the endosomal system via endocytosis, after which they are either recycled back to the plasma membrane or degraded at the lysosome. In T cells, lipopolysaccharide‐responsive beige‐like anchor protein (LRBA) binds directly to the cytotoxic T lymphocyte antigen 4 (CTLA‐4), a checkpoint immune molecule, to prevent CTLA‐4 lysosomal degradation and promote its vesicle recycling. LRBA has different physiological functions in renal collecting ducts. LRBA and aquaporin‐2 (AQP2) water channels were colocalized on the recycling endosome in vivo in the absence of the anti‐diuretic hormone vasopressin. LRBA promoted vasopressin‐induced AQP2 trafficking, increasing water reabsorption from urine via AQP2. LRBA determined renal responsiveness to vasopressin at recycling endosomes. LRBA is a ubiquitously expressed anchor protein. LRBA signalosomes might regulate membrane trafficking of several constitutively recycled proteins at recycling endosomes.

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Section: Discussionmentioning

confidence: 99%

LRBA signalosomes activate vasopressin‐induced AQP2 trafficking at recycling endosomes

Yanagawa,

Hara,

Ando

et al. 2023

The Journal of Physiology

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Regulatory T cells as crucial trigger and potential target for hyperprogressive disease subsequent to PD-1/PD-L1 blockade for cancer treatment

Ren,

Yang,

Zhu

et al. 2024

International Immunopharmacology

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The role of PD-1 signaling in health and immune-related diseases

et al. 2023

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Programmed cell death 1 receptor (PD-1) and its ligands constitute an inhibitory pathway to mediate the mechanism of immune tolerance and provide immune homeostasis. Significantly, the binding partners of PD-1 and its associated ligands are diverse, which facilitates immunosuppression in cooperation with other immune checkpoint proteins. Accumulating evidence has demonstrated the important immunosuppressive role of the PD-1 axis in the tumor microenvironment and in autoimmune diseases. In addition, PD-1 blockades have been approved to treat various cancers, including solid tumors and hematological malignancies. Here, we provide a comprehensive review of the PD-1 pathway, focusing on the structure and expression of PD-1, programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2); the diverse biological functions of PD-1 signaling in health and immune-related diseases (including tumor immunity, autoimmunity, infectious immunity, transplantation immunity, allergy and immune privilege); and immune-related adverse events related to PD-1 and PD-L1 inhibitors.

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Two CTLA-4 ligands, separate pHates

Cited by 3 publications

References 12 publications

LRBA signalosomes activate vasopressin‐induced AQP2 trafficking at recycling endosomes

LRBA signalosomes activate vasopressin‐induced AQP2 trafficking at recycling endosomes

Regulatory T cells as crucial trigger and potential target for hyperprogressive disease subsequent to PD-1/PD-L1 blockade for cancer treatment

The role of PD-1 signaling in health and immune-related diseases

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