ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells
Immune cells exhibit low-level, constitutive signaling at rest (tonic signaling). Such tonic signals are required for fundamental processes, including the survival of B lymphocytes, but when they are elevated by genetic or environmental causes, they can lead to autoimmunity. Events that control ongo...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2021-12-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.149376 |
| _version_ | 1811227192698339328 |
|---|---|
| author | Gabriella Leung Yuhuan Zhou Philip Ostrowski Sivakami Mylvaganam Parastoo Boroumand Daniel J. Mulder Conghui Guo Aleixo M. Muise Spencer A. Freeman |
| author_facet | Gabriella Leung Yuhuan Zhou Philip Ostrowski Sivakami Mylvaganam Parastoo Boroumand Daniel J. Mulder Conghui Guo Aleixo M. Muise Spencer A. Freeman |
| author_sort | Gabriella Leung |
| collection | DOAJ |
| description | Immune cells exhibit low-level, constitutive signaling at rest (tonic signaling). Such tonic signals are required for fundamental processes, including the survival of B lymphocytes, but when they are elevated by genetic or environmental causes, they can lead to autoimmunity. Events that control ongoing signal transduction are, therefore, tightly regulated by submembrane cytoskeletal polymers like F-actin. The actin-binding proteins that underpin the process, however, are poorly described. By investigating patients with ARPC1B deficiency, we report that ARPC1B-containing ARP2/3 complexes are stimulated by Wiskott Aldrich Syndrome protein (WASP) to nucleate the branched actin networks that control tonic signaling from the B cell receptor (BCR). Despite an upregulation of ARPC1A, ARPC1B-deficient cells were not capable of WASP-mediated nucleation by ARP2/3, and this caused the loss of WASP-dependent structures, including podosomes in macrophages and lamellipodia in B cells. In the B cell compartment, ARPC1B deficiency also led to weakening of the cortical F-actin cytoskeleton that normally curtails the diffusion of BCRs and ultimately resulted in increased tonic lipid signaling, oscillatory calcium release from the endoplasmic reticulum (ER), and phosphorylated Akt. These events contributed to skewing the threshold for B cell activation in response to microbial-associated molecular patterns (MAMPs). Thus, ARPC1B is critical for ARP2/3 complexes to control steady-state signaling of immune cells. |
| first_indexed | 2024-04-12T09:38:19Z |
| format | Article |
| id | doaj.art-f48f1a9c766d467ea623c026d7219255 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T09:38:19Z |
| publishDate | 2021-12-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-f48f1a9c766d467ea623c026d72192552022-12-22T03:38:10ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-12-01623ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cellsGabriella LeungYuhuan ZhouPhilip OstrowskiSivakami MylvaganamParastoo BoroumandDaniel J. MulderConghui GuoAleixo M. MuiseSpencer A. FreemanImmune cells exhibit low-level, constitutive signaling at rest (tonic signaling). Such tonic signals are required for fundamental processes, including the survival of B lymphocytes, but when they are elevated by genetic or environmental causes, they can lead to autoimmunity. Events that control ongoing signal transduction are, therefore, tightly regulated by submembrane cytoskeletal polymers like F-actin. The actin-binding proteins that underpin the process, however, are poorly described. By investigating patients with ARPC1B deficiency, we report that ARPC1B-containing ARP2/3 complexes are stimulated by Wiskott Aldrich Syndrome protein (WASP) to nucleate the branched actin networks that control tonic signaling from the B cell receptor (BCR). Despite an upregulation of ARPC1A, ARPC1B-deficient cells were not capable of WASP-mediated nucleation by ARP2/3, and this caused the loss of WASP-dependent structures, including podosomes in macrophages and lamellipodia in B cells. In the B cell compartment, ARPC1B deficiency also led to weakening of the cortical F-actin cytoskeleton that normally curtails the diffusion of BCRs and ultimately resulted in increased tonic lipid signaling, oscillatory calcium release from the endoplasmic reticulum (ER), and phosphorylated Akt. These events contributed to skewing the threshold for B cell activation in response to microbial-associated molecular patterns (MAMPs). Thus, ARPC1B is critical for ARP2/3 complexes to control steady-state signaling of immune cells.https://doi.org/10.1172/jci.insight.149376Cell biologyImmunology |
| spellingShingle | Gabriella Leung Yuhuan Zhou Philip Ostrowski Sivakami Mylvaganam Parastoo Boroumand Daniel J. Mulder Conghui Guo Aleixo M. Muise Spencer A. Freeman ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells JCI Insight Cell biology Immunology |
| title | ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells |
| title_full | ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells |
| title_fullStr | ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells |
| title_full_unstemmed | ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells |
| title_short | ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells |
| title_sort | arpc1b binds wasp to control actin polymerization and curtail tonic signaling in b cells |
| topic | Cell biology Immunology |
| url | https://doi.org/10.1172/jci.insight.149376 |
| work_keys_str_mv | AT gabriellaleung arpc1bbindswasptocontrolactinpolymerizationandcurtailtonicsignalinginbcells AT yuhuanzhou arpc1bbindswasptocontrolactinpolymerizationandcurtailtonicsignalinginbcells AT philipostrowski arpc1bbindswasptocontrolactinpolymerizationandcurtailtonicsignalinginbcells AT sivakamimylvaganam arpc1bbindswasptocontrolactinpolymerizationandcurtailtonicsignalinginbcells AT parastooboroumand arpc1bbindswasptocontrolactinpolymerizationandcurtailtonicsignalinginbcells AT danieljmulder arpc1bbindswasptocontrolactinpolymerizationandcurtailtonicsignalinginbcells AT conghuiguo arpc1bbindswasptocontrolactinpolymerizationandcurtailtonicsignalinginbcells AT aleixommuise arpc1bbindswasptocontrolactinpolymerizationandcurtailtonicsignalinginbcells AT spencerafreeman arpc1bbindswasptocontrolactinpolymerizationandcurtailtonicsignalinginbcells |