An essential role for the MAL protein in targeting Lck to the plasma membrane of human T lymphocytes

Antón, Olga M.; Batista, Alicia; Millán, Jaime; Andrés-Delgado, Laura; Puertollano, Rosa; Correas, Isabel; Alonso, Miguel A.

doi:10.1083/jcb1836oia15

Cited by 17 publications

(35 citation statements)

References 1 publication

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“…The exact nature of the pericentrosomal pool of Lck is not entirely clear. Yet, Lck is associated with vesicles that bear the Rab11 GTPase, the uncoordinated 119 protein (UNC119) and the tetraspanning transmembrane protein MAL . Upon activation, the endocytic pool of Lck is recruited to the IS …”

Section: Intracellular Pools Of Tcr and Associated Signaling Proteinsmentioning

confidence: 99%

“…MAL is a highly hydrophobic integral protein expressed by T lymphocytes and polarized epithelial cells, which, like Lck, partitions into detergent‐resistant membrane fractions . At steady state, MAL colocalizes with the Rab11 positive pool of Lck and upon IS formation MAL travels together with Lck toward the plasma membrane . In epithelial cells, MAL silencing impairs the transport of proteins to the apical surface and their missorting at the basolateral surface .…”

Section: Intracellular Pools Of Tcr and Associated Signaling Proteinsmentioning

confidence: 99%

“…In epithelial cells, MAL silencing impairs the transport of proteins to the apical surface and their missorting at the basolateral surface . In T lymphocytes, MAL silencing induces a missorting of Lck, which is not partitioned anymore in the detergent‐resistant membranes, is not distributed at the cell surface and is retained in endosomes . MAL interacts with the inverted formin‐2 (INF2), a protein of the formin family, which promotes actin filament assembly and also binds and bundles microtubules .…”

Section: Intracellular Pools Of Tcr and Associated Signaling Proteinsmentioning

confidence: 99%

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Is there a place and role for endocytic TCR signaling?

Saveanu

Zucchetti

Evnouchidou

et al. 2019

Immunological Reviews

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Team: Integrative analysis of T cell activation, Batiment Burg, 5th floor, 12 rue LHOMOND, Abstract T-lymphocyte activation relies on the cognate recognition by the TCR of the MHCassociated peptide ligand (pMHC) presented at the surface of an antigen-presenting cell (APC). This leads to the dynamic formation of a cognate contact between the T lymphocyte and the APC: the immune synapse (IS). Engagement of the TCR by the pMHC in the synaptic zone induces a cascade of signaling events leading to phosphorylation and dephosphorylation of proteins and lipids, which ultimately shapes the response of T lymphocytes. Although the engagement of the T-cell receptor (TCR)takes place at the plasma membrane, the TCR/CD3 complexes and the signaling molecules involved in transduction of the TCR signal are also present in intracellular membrane pools. These pools, which are both endocytic and exocytic, have tentatively been characterized by several groups including ours. We will herein summarize what is known on the intracellular pools of TCR signaling components. We will discuss their origin and the mechanisms involved in their mobility at the IS. Finally, we will propose several hypotheses concerning the functional role(s) that these intracellular pools might play in T-cell activation. We will also discuss the tools that could be used to test these hypotheses. K E Y W O R D Sendosomes, Immune synapse, Intracellular trafficking, TCR, T lymphocyte

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Section: Intracellular Pools Of Tcr and Associated Signaling Proteinsmentioning

confidence: 99%

Section: Intracellular Pools Of Tcr and Associated Signaling Proteinsmentioning

confidence: 99%

Section: Intracellular Pools Of Tcr and Associated Signaling Proteinsmentioning

confidence: 99%

See 1 more Smart Citation

Is there a place and role for endocytic TCR signaling?

Saveanu

Zucchetti

Evnouchidou

et al. 2019

Immunological Reviews

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“…Indeed, Lck, TCRζ, and LAT are associated with endosomal vesicular compartments whose traffic is controlled by different regulators, including Rab GTPases, intraflagellar transport proteins, and SNAREs. Perturbation of these regulatory proteins impairs immunological synapse formation and function (Das et al , ; Anton et al , ; Patino‐Lopez et al , ; Finetti et al , , ; Martin‐Cofreces et al , ; Larghi et al , ; Soares et al , ).…”

Section: Introductionmentioning

confidence: 99%

Rac1‐Rab11‐ FIP 3 regulatory hub coordinates vesicle traffic with actin remodeling and T‐cell activation

et al. 2016

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The immunological synapse generation and function is the result of a T-cell polarization process that depends on the orchestrated action of the actin and microtubule cytoskeleton and of intracellular vesicle traffic. However, how these events are coordinated is ill defined. Since Rab and Rho families of GTPases control intracellular vesicle traffic and cytoskeleton reorganization, respectively, we investigated their possible interplay. We show here that a significant fraction of Rac1 is associated with Rab11-positive recycling endosomes. Moreover, the Rab11 effector FIP3 controls Rac1 intracellular localization and Rac1 targeting to the immunological synapse. FIP3 regulates, in a Rac1-dependent manner, key morphological events, like T-cell spreading and synapse symmetry. Finally, Rab11-/FIP3-mediated regulation is necessary for T-cell activation leading to cytokine production. Therefore, Rac1 endosomal traffic is key to regulate T-cell activation.

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“…How SFKs are subsequently transported to the PM is largely unclear, but the degree of palmitoylation represents a critical determinant since dually palmitoylated SFKs use transport pathways distinct from those with one or no palmitoylation site (Sato et al ., ). In the case of Lck, components of the transport machinery for PM targeting such as the protein MAL, the formin actin nucleator INF2, the adaptor protein Unc119, and the GTPase Rab11 have been identified (Gorska et al ., 2004; 2009; 2010; Anton et al ., ; Andres‐Delgado et al ., ). Whether Fyn relies on the same machinery and how these individual components facilitate PM targeting is unclear.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Nef disrupts membrane-microdomain-associated anterograde transport for plasma membrane delivery of selected Src family kinases

et al. 2013

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Summary HIV-1 Nef, an essential factor in AIDS pathogenesis, boosts virus replication in vivo. As one of its activities in CD4+ T-lymphocytes, Nef potently retargets the Src family kinase (SFK) Lck but not closely related Fyn from the plasma membrane to recycling endosomes and the trans-Golgi network to tailor T-cell activation and optimize virus replication. Investigating the underlying mechanism we find Lck retargeting involves removal of the kinase from membrane microdomains. Moreover, Nef interferes with rapid vesicular transport of Lck to block anterograde transport and plasma membrane delivery of newly synthesized Lck. The sensitivity of Lck to Nef does not depend on functional domains of Lck but requires membrane insertion of the kinase. Surprisingly, the short N-terminal SH4 domain membrane anchor of Lck is necessary and sufficient to confer sensitivity to Nef-mediated anterograde transport block and microdomain extraction. In contrast, the SH4 domain of Fyn is inert to Nef-mediated manipulation. Nef thus interferes with a specialized membrane microdomainassociated pathway for plasma membrane delivery of newly synthesized Lck whose specificity is determined by the affinity of cargo for these sorting platforms. These results provide new insight into the mechanism of Nef action and the pathways used for SFK plasma membrane delivery.

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An essential role for the MAL protein in targeting Lck to the plasma membrane of human T lymphocytes

Cited by 17 publications

References 1 publication

Is there a place and role for endocytic TCR signaling?

Is there a place and role for endocytic TCR signaling?

Rac1‐Rab11‐ FIP 3 regulatory hub coordinates vesicle traffic with actin remodeling and T‐cell activation

HIV-1 Nef disrupts membrane-microdomain-associated anterograde transport for plasma membrane delivery of selected Src family kinases

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