β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4

D’Agostino, Gianluca; Artinger, Marc; Locati, Massimo; Perez, Laurent; Legler, Daniel F.; Bianchi, Marco E.; Rüegg, Curzio; Thelen, Marcus; Marchese, Adriano; Rocchi, Marco; Cecchinato, Valentina; Uguccioni, Mariagrazia

doi:10.3389/fimmu.2020.550824

Cited by 20 publications

(23 citation statements)

References 64 publications

(111 reference statements)

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“…Impaired chemokine receptor desensitization has been also associated with random rather than directed migration ( 33 ). Additionally, although some reports implicate β-arrestins in chemokine-mediated cell migration, only β-arrestin1 has been associated to CXCL12-induced directed cell migration ( 34 , 35 ). We thus questioned whether defects in β-arrestin activation might explain the lack of ligand-mediated CXCR4 R334X nanoclustering and directed cell migration.…”

Section: Resultsmentioning

confidence: 99%

“…β-Arrestins are involved in chemokine receptor desensitization and internalization ( 44 ), but they also have a scaffolding role for a number of signaling molecules ( 45 , 46 ) and participate in actin reorganization and chemotaxis processes ( 28 , 47 , 48 ). In vivo studies have demonstrated the involvement of β-arrestins in tumor cell migration and metastasis ( 49 ), and in the recruitment of immune cells to sites of inflammation ( 50 ), although only β-arrestin1 participates in chemokine-mediated directed cell migration ( 35 ). There is also evidence supporting a role for β-arrestins in the spatial control of actin assembly events at the leading edge of primary leukocytes and cultured cells ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

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Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients

García‐Cuesta

Rodrı́guez-Frade

Gardeta

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance New imaging-based approaches are incorporating new concepts to our knowledge of biological processes. The analysis of receptor dynamics involved in cell movement using single-particle tracking demonstrates that cells require chemokine-mediated receptor clustering to sense appropriately chemoattractant gradients. Here, we report that this process does not occur in T cells expressing CXCR4 R334X , a mutant form of CXCR4 linked to WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis). The underlaying molecular mechanism involves inappropriate actin cytoskeleton remodeling due to the inadequate β-arrestin1 activation by CXCR4 R334X , which alters its lateral mobility and spatial organization. These defects, associated to CXCR4 R334X expression, contribute to the retention of hematopoietic precursors in bone marrow niches and explain the severe immunological symptoms associated with WHIM syndrome.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients

García‐Cuesta

Rodrı́guez-Frade

Gardeta

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, the oxidation state of its cysteines (two in the A-box, one in the B-box) modulates its biological activity in the extracellular environment ( Figures 1 , 3 ) ( 35 ). Only fully reduced HMGB1 and the non-oxidizable HMGB1 mutant 3S, in which three serine residues replace cysteines, induce chemotaxis by binding CXCL12 through the CXCR4 receptor [maintained at the surface by the CXCL12/HMGB1 heterodimer ( 36 )], and recruit stem cells to orchestrate tissue regeneration ( 37 ) ( Figure 3 ). Besides this particular activity, the signaling activity of HMGB1 and its complexes (with nucleic acids, LPS, …) is mainly mediated by the receptor for advanced glycation end products (RAGE) and TLRs, although a larger range of receptors may be considered ( 38 , 39 ).…”

Section: Molecular Bases On Complement and Hmgb1 Multiple Functions W...mentioning

confidence: 99%

Complement System and Alarmin HMGB1 Crosstalk: For Better or Worse

et al. 2022

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Our immune system responds to infectious (PAMPs) and tissue damage (DAMPs) signals. The complement system and alarmin High-Mobility Group Box 1 (HMGB1) are two powerful soluble actors of human host defense and immune surveillance. These systems involve molecular cascades and amplification loops for their signaling or activation. Initially activated as alarm raising systems, their function can be finally switched towards inflammation resolution, where they sustain immune maturation and orchestrate repair mechanisms, opening the way back to homeostasis. However, when getting out of control, these defense systems can become deleterious and trigger serious cellular and tissue damage. Therefore, they can be considered as double-edged swords. The close interaction between the complement and HMGB1 pathways is described here, as well as their traditional and non-canonical roles, their functioning at different locations and their independent and collective impact in different systems both in health and disease. Starting from these systems and interplay at the molecular level (when elucidated), we then provide disease examples to better illustrate the signs and consequences of their roles and interaction, highlighting their importance and possible vicious circles in alarm raising and inflammation, both individually or in combination. Although this integrated view may open new therapeutic strategies, future challenges have to be faced because of the remaining unknowns regarding the molecular mechanisms underlying the fragile molecular balance which can drift towards disease or return to homeostasis, as briefly discussed at the end.

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“…CXCR4 is a member of G protein-coupled receptors, and its major ligand is CXCL12. After binding to CXCL12, HMGB1 forms a heterocomplex and binds to CXCR4, inducing the recruitment of inflammatory cells to injured tissues [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

High Mobility Group Box 1: Biological Functions and Relevance in Oxidative Stress Related Chronic Diseases

Taverna

Tonacci

Ferraro

et al. 2022

Cells

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In the early 1970s, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and named high-mobility group (HMG) proteins. High-mobility group box 1 (HMGB1) is the most studied HMG protein that detects and coordinates cellular stress response. The biological function of HMGB1 depends on its subcellular localization and expression. It plays a critical role in the nucleus and cytoplasm as DNA chaperone, chromosome gatekeeper, autophagy maintainer, and protector from apoptotic cell death. HMGB1 also functions as an extracellular alarmin acting as a damage-associated molecular pattern molecule (DAMP). Recent findings describe HMGB1 as a sophisticated signal of danger, with a pleiotropic function, which is useful as a clinical biomarker for several disorders. HMGB1 has emerged as a mediator in acute and chronic inflammation. Furthermore, HMGB1 targeting can induce beneficial effects on oxidative stress related diseases. This review focus on HMGB1 redox status, localization, mechanisms of release, binding with receptors, and its activities in different oxidative stress-related chronic diseases. Since a growing number of reports show the key role of HMGB1 in socially relevant pathological conditions, to our knowledge, for the first time, here we analyze the scientific literature, evaluating the number of publications focusing on HMGB1 in humans and animal models, per year, from 2006 to 2021 and the number of records published, yearly, per disease and category (studies on humans and animal models).

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β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4

Cited by 20 publications

References 64 publications

Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients

Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients

Complement System and Alarmin HMGB1 Crosstalk: For Better or Worse

High Mobility Group Box 1: Biological Functions and Relevance in Oxidative Stress Related Chronic Diseases

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