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Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome.

Cotta-de-Almeida V, Dupré L, Guipouy D, Vasconcelos Z - Front Immunol (2015)

Bottom Line: Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches.Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system.These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions.

View Article: PubMed Central - PubMed

Affiliation: Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.

ABSTRACT
Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches. Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system. In this review, we highlight the research that has focused over the last 20 years on T lymphocytes from Wiskott-Aldrich syndrome (WAS) patients. WAS T lymphocytes are defective for the WAS protein (WASP), a regulator of actin cytoskeleton remodeling. Therefore, study of WAS T lymphocytes has helped to grasp that many steps of T lymphocyte activation and function depend on the crosstalk between membrane receptors and the actin cytoskeleton. These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions. The recent concept that WASP also works as a regulator of transcription within the nucleus is an illustration of the complexity of signal integration in T lymphocytes. Finally, this review will discuss how further study of WAS may contribute to solve novel challenges of T lymphocyte biology.

No MeSH data available.


Related in: MedlinePlus

Wiskott–Aldrich syndrome protein activation, molecular partners, and cytoskeleton remodeling. In its basal state, the Wiskott–Aldrich syndrome protein (WASP) is auto-inhibited due to intramolecular interaction between its verprolin-homology domain–cofilin homology domain–acidic region (VCA) domain and its GTPase-binding domain (GBD). The association of WASP-interacting protein (WIP) with the WASP homology 1 (WH1) domain stabilizes the auto-inhibited form. Upon activation of a wide range of cell surface receptors (detailed in Figure 2), the Rho family GTPase cell division cycle 2 (CDC42) binds to the GBD, which causes the release of the VCA. Additional WASP activators include the proline–serine–threonine phosphatase-interacting protein 1 (PSTPIP1) and phosphatidylinositol-4,5-biphosphate (PIP2) that, respectively, bind the polyproline (PPP) domain and the basic (B) domain. Stability of active WASP is dependent on the phosphorylation status of tyrosine residue 291 (Y291), which is regulated by Src family tyrosine kinases and the tyrosine–protein phosphatase non-receptor type 12 (PTPN12). Active WASP binds, via its VCA, the actin-related protein 2 and 3 (ARP2-ARP3) complex and monomeric actin to produce a new actin branch. Dynamical actin remodeling relies on a balance between WASP activation and degradation, the latter being regulated by ubiquitination and mediated by the proteasome.
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Figure 1: Wiskott–Aldrich syndrome protein activation, molecular partners, and cytoskeleton remodeling. In its basal state, the Wiskott–Aldrich syndrome protein (WASP) is auto-inhibited due to intramolecular interaction between its verprolin-homology domain–cofilin homology domain–acidic region (VCA) domain and its GTPase-binding domain (GBD). The association of WASP-interacting protein (WIP) with the WASP homology 1 (WH1) domain stabilizes the auto-inhibited form. Upon activation of a wide range of cell surface receptors (detailed in Figure 2), the Rho family GTPase cell division cycle 2 (CDC42) binds to the GBD, which causes the release of the VCA. Additional WASP activators include the proline–serine–threonine phosphatase-interacting protein 1 (PSTPIP1) and phosphatidylinositol-4,5-biphosphate (PIP2) that, respectively, bind the polyproline (PPP) domain and the basic (B) domain. Stability of active WASP is dependent on the phosphorylation status of tyrosine residue 291 (Y291), which is regulated by Src family tyrosine kinases and the tyrosine–protein phosphatase non-receptor type 12 (PTPN12). Active WASP binds, via its VCA, the actin-related protein 2 and 3 (ARP2-ARP3) complex and monomeric actin to produce a new actin branch. Dynamical actin remodeling relies on a balance between WASP activation and degradation, the latter being regulated by ubiquitination and mediated by the proteasome.

Mentions: A close analysis of WASP reveals a molecular hub organized as a five-domain structured molecule (Figure 1). The first N-terminal domain, WASP homology 1 (WH1; also defined as EVH1, for ENA/VASP homology 1) binds to a proline repeat motif present in WASP-interacting protein (WIP) and mediates a molecular interaction regarded as critical for keeping a stable and auto-inhibited WASP conformation. The basic region also participates in the regulation of WASP conformational status, as it binds to the phosphoinositide PIP2 (phosphatidylinositol-4,5-biphosphate), which acts synergistically with the small GTPase Cdc42 to activate WASP (8). The GTPase binding domain (GBD), in a non-activated state of the WASP molecule, is found in an intramolecular hydrophobic link with the C-terminal VCA (composed by the verprolin-homology, central hydrophobic, and acidic regions) domain. Upon cell activation, GBD is the critical binding site for the active Cdc42-GTP, and such an interaction leads to a conformational change that releases the VCA domain, shifting auto-inhibited WASP to an active molecule. The proline-rich region contains several sites for binding of Src homology 3 (SH3) domain, playing a role as a central core for docking of various SH3 domain-containing proteins. The C-terminal VCA forms the actin-nucleating region of WASP. It binds both actin monomers and the Arp2/3 complex, which is composed of seven proteins that work together to assemble branches of actin that grow out of a pre-existing filament. Altogether, WASP binding regions provide a molecular hub for associations with several proteins that integrate distinct signals brought together during cellular WASP activity (7, 9).


Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome.

Cotta-de-Almeida V, Dupré L, Guipouy D, Vasconcelos Z - Front Immunol (2015)

Wiskott–Aldrich syndrome protein activation, molecular partners, and cytoskeleton remodeling. In its basal state, the Wiskott–Aldrich syndrome protein (WASP) is auto-inhibited due to intramolecular interaction between its verprolin-homology domain–cofilin homology domain–acidic region (VCA) domain and its GTPase-binding domain (GBD). The association of WASP-interacting protein (WIP) with the WASP homology 1 (WH1) domain stabilizes the auto-inhibited form. Upon activation of a wide range of cell surface receptors (detailed in Figure 2), the Rho family GTPase cell division cycle 2 (CDC42) binds to the GBD, which causes the release of the VCA. Additional WASP activators include the proline–serine–threonine phosphatase-interacting protein 1 (PSTPIP1) and phosphatidylinositol-4,5-biphosphate (PIP2) that, respectively, bind the polyproline (PPP) domain and the basic (B) domain. Stability of active WASP is dependent on the phosphorylation status of tyrosine residue 291 (Y291), which is regulated by Src family tyrosine kinases and the tyrosine–protein phosphatase non-receptor type 12 (PTPN12). Active WASP binds, via its VCA, the actin-related protein 2 and 3 (ARP2-ARP3) complex and monomeric actin to produce a new actin branch. Dynamical actin remodeling relies on a balance between WASP activation and degradation, the latter being regulated by ubiquitination and mediated by the proteasome.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4321635&req=5

Figure 1: Wiskott–Aldrich syndrome protein activation, molecular partners, and cytoskeleton remodeling. In its basal state, the Wiskott–Aldrich syndrome protein (WASP) is auto-inhibited due to intramolecular interaction between its verprolin-homology domain–cofilin homology domain–acidic region (VCA) domain and its GTPase-binding domain (GBD). The association of WASP-interacting protein (WIP) with the WASP homology 1 (WH1) domain stabilizes the auto-inhibited form. Upon activation of a wide range of cell surface receptors (detailed in Figure 2), the Rho family GTPase cell division cycle 2 (CDC42) binds to the GBD, which causes the release of the VCA. Additional WASP activators include the proline–serine–threonine phosphatase-interacting protein 1 (PSTPIP1) and phosphatidylinositol-4,5-biphosphate (PIP2) that, respectively, bind the polyproline (PPP) domain and the basic (B) domain. Stability of active WASP is dependent on the phosphorylation status of tyrosine residue 291 (Y291), which is regulated by Src family tyrosine kinases and the tyrosine–protein phosphatase non-receptor type 12 (PTPN12). Active WASP binds, via its VCA, the actin-related protein 2 and 3 (ARP2-ARP3) complex and monomeric actin to produce a new actin branch. Dynamical actin remodeling relies on a balance between WASP activation and degradation, the latter being regulated by ubiquitination and mediated by the proteasome.
Mentions: A close analysis of WASP reveals a molecular hub organized as a five-domain structured molecule (Figure 1). The first N-terminal domain, WASP homology 1 (WH1; also defined as EVH1, for ENA/VASP homology 1) binds to a proline repeat motif present in WASP-interacting protein (WIP) and mediates a molecular interaction regarded as critical for keeping a stable and auto-inhibited WASP conformation. The basic region also participates in the regulation of WASP conformational status, as it binds to the phosphoinositide PIP2 (phosphatidylinositol-4,5-biphosphate), which acts synergistically with the small GTPase Cdc42 to activate WASP (8). The GTPase binding domain (GBD), in a non-activated state of the WASP molecule, is found in an intramolecular hydrophobic link with the C-terminal VCA (composed by the verprolin-homology, central hydrophobic, and acidic regions) domain. Upon cell activation, GBD is the critical binding site for the active Cdc42-GTP, and such an interaction leads to a conformational change that releases the VCA domain, shifting auto-inhibited WASP to an active molecule. The proline-rich region contains several sites for binding of Src homology 3 (SH3) domain, playing a role as a central core for docking of various SH3 domain-containing proteins. The C-terminal VCA forms the actin-nucleating region of WASP. It binds both actin monomers and the Arp2/3 complex, which is composed of seven proteins that work together to assemble branches of actin that grow out of a pre-existing filament. Altogether, WASP binding regions provide a molecular hub for associations with several proteins that integrate distinct signals brought together during cellular WASP activity (7, 9).

Bottom Line: Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches.Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system.These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions.

View Article: PubMed Central - PubMed

Affiliation: Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.

ABSTRACT
Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches. Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system. In this review, we highlight the research that has focused over the last 20 years on T lymphocytes from Wiskott-Aldrich syndrome (WAS) patients. WAS T lymphocytes are defective for the WAS protein (WASP), a regulator of actin cytoskeleton remodeling. Therefore, study of WAS T lymphocytes has helped to grasp that many steps of T lymphocyte activation and function depend on the crosstalk between membrane receptors and the actin cytoskeleton. These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions. The recent concept that WASP also works as a regulator of transcription within the nucleus is an illustration of the complexity of signal integration in T lymphocytes. Finally, this review will discuss how further study of WAS may contribute to solve novel challenges of T lymphocyte biology.

No MeSH data available.


Related in: MedlinePlus