GPR174 signals via G<i>α</i>s to control a CD86-containing gene expression program in B cells

Wolf, Elise W; Howard, Zachary P.; Duan, Lihui; Tam, H.K.; Xu, Ying; Cyster, Jason G.

doi:10.1073/pnas.2201794119

Cited by 12 publications

(10 citation statements)

References 77 publications

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“…3E), including the genes encoding the major gut-homing integrin, integrin beta-7 (ITGB7), and—perhaps more unexpectedly—transcripts encoding the chylomicron apolipoprotein ApoE or the lysophosphatidylserine receptor Gpr174 (Fig. 3F), whose functions in B cells are not clear ( 45 ). The expression of some transcripts normalized after a day or two (module no.…”

Section: Resultsmentioning

confidence: 99%

A dynamic atlas of immunocyte migration from the gut

Galván-Peña,

Zhu,

Hanna

et al. 2024

Sci. Immunol.

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Dysbiosis in the gut microbiota affects several systemic diseases, possibly by driving the migration of perturbed intestinal immunocytes to extraintestinal tissues. Combining Kaede photoconvertible mice and single-cell genomics, we generated a detailed map of migratory trajectories from the colon, at baseline, and in several models of intestinal and extraintestinal inflammation. All lineages emigrated from the colon in an S1P-dependent manner. B lymphocytes represented the largest contingent, with the unexpected circulation of nonexperienced follicular B cells, which carried a gut-imprinted transcriptomic signature. T cell emigration included distinct groups of RORγ + and IEL-like CD160 + subsets. Gut inflammation curtailed emigration, except for dendritic cells disseminating to lymph nodes. Colon-emigrating cells distributed differentially to distinct sites of extraintestinal models of inflammation (psoriasis-like skin, arthritic synovium, and tumors). Thus, specific cellular trails originating in the gut and influenced by microbiota may shape peripheral immunity in varied ways.

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Section: Resultsmentioning

confidence: 99%

A dynamic atlas of immunocyte migration from the gut

Galván-Peña,

Zhu,

Hanna

et al. 2024

Sci. Immunol.

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“…The distinctive G s engagement of GPR174 is totally out of our expectations. The extensive polar interactions between receptor/Gα s and the deepest insertion of αH5 into the intracellular core of the receptor suggest that GPR174 uses a unique way to bind and engage Gα s , and those observations also indicate that G s is tightly packed against receptor, and this may explain the high level of constitutive activity of GPR174 11,37 and weak ligand-induced G s dissociation activity (see the section "Methods" functional assay). We used the NanoBiT strategy in our complex assembling, the strategy only increases the local concentration of binding partners and cannot force an interaction that does not exist in nature, evidenced by the identical structures of GPR110/G s complexes solved with or without the NanoBiT strategy recently 38,39 .…”

Section: Discussionmentioning

confidence: 99%

Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation

et al. 2023

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Lysophosphatidylserine (LysoPS) is a lipid mediator that induces multiple cellular responses through binding to GPR174. Here, we present the cryo-electron microscopy (cryo-EM) structure of LysoPS-bound human GPR174 in complex with Gs protein. The structure reveals a ligand recognition mode, including the negatively charged head group of LysoPS forms extensive polar interactions with surrounding key residues of the ligand binding pocket, and the L-serine moiety buries deeply into a positive charged cavity in the pocket. In addition, the structure unveils a partially open pocket on transmembrane domain helix (TM) 4 and 5 for a lateral entry of ligand. Finally, the structure reveals a Gs engaging mode featured by a deep insertion of a helix 5 (αH5) and extensive polar interactions between receptor and αH5. Taken together, the information revealed by our structural study provides a framework for understanding LysoPS signaling and a rational basis for designing LysoPS receptor-targeting drugs.

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“…253 Interestingly, very recently, it has also been demonstrated that in vivo, lyso-PS acts via GPR174-Gα s G-proteins to also promote the expression of CD86 on B cells, thereby fine-tuning B cell responses during conditions of inflammation. 255 While the direct involvement of lyso-PS in some immunological processes has not yet been proven, GPR174's role in these processes has now been well-established. For example, the loss of GPR174 in mice prevents the progression of sepsis and the cytokine storm associated with it.…”

Section: G-protein Coupled Receptor 174 (Gpr174)mentioning

confidence: 99%

Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases

Chakraborty,

Kamat

2024

Chem. Rev.

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Lysophosphatidylserine (lyso-PS) has emerged as yet another important signaling lysophospholipid in mammals, and deregulation in its metabolism has been directly linked to an array of human autoimmune and neurological disorders. It has an indispensable role in several biological processes in humans, and therefore, cellular concentrations of lyso-PS are tightly regulated to ensure optimal signaling and functioning in physiological settings. Given its biological importance, the past two decades have seen an explosion in the available literature toward our understanding of diverse aspects of lyso-PS metabolism and signaling and its association with human diseases. In this Review, we aim to comprehensively summarize different aspects of lyso-PS, such as its structure, biodistribution, chemical synthesis, and SAR studies with some synthetic analogs. From a biochemical perspective, we provide an exhaustive coverage of the diverse biological activities modulated by lyso-PSs, such as its metabolism and the receptors that respond to them in humans. We also briefly discuss the human diseases associated with aberrant lyso-PS metabolism and signaling and posit some future directions that may advance our understanding of lyso-PS-mediated mammalian physiology.

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GPR174 signals via Gαs to control a CD86-containing gene expression program in B cells

Cited by 12 publications

References 77 publications

A dynamic atlas of immunocyte migration from the gut

A dynamic atlas of immunocyte migration from the gut

Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation

Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases

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