γ2 and γ1AP-1 complexes: Different essential functions and regulatory mechanisms in clathrin-dependent protein sorting

Zizioli, Daniela; Geumann, Constanze; Kratzke, Manuel; Mishra, Ratnakar; Borsani, G.; Finazzi, Dario; Candiello, Ermes; Schu, Peter

doi:10.1016/j.ejcb.2017.03.008

Cited by 11 publications

(18 citation statements)

References 70 publications

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“…Our group reported that the Nef-mediated downregulation of CD4 requires the function of AP-1␥2 but not . Similarly, knockdown of either ␥1 or ␥2 leads to distinct phenotypes in zebrafish development (28). Here, however, we describe that the specific depletion of either ␥1 or ␥2 compromises HLA-A downregulation by Nef, via a process in which two different AP-1 subunits interact with the same molecules but with nonredundant functions.…”

Section: Discussionmentioning

confidence: 78%

“…Several studies using RNA interference demonstrated that the expression of both 1A and ␥1 subunits is required for the downregulation of MHC-I by Nef (12)(13)(14)(15)23). Interestingly, there is growing evidence that some of these isoforms may combine to form functionally distinct AP-1 complexes (24)(25)(26)(27)(28). Indeed, we have previously demonstrated that a functional variant of AP-1 that contains ␥2 (AP-1␥2), but not the AP-1␥1 complex, is required for efficient downregulation of CD4 by Nef (26).…”

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confidence: 99%

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Two Functional Variants of AP-1 Complexes Composed of either γ2 or γ1 Subunits Are Independently Required for Major Histocompatibility Complex Class I Downregulation by HIV-1 Nef

Tavares

Carvalho

Costa

et al. 2020

J Virol

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The HIV-1 accessory protein Nef downregulates the cell surface expression of major histocompatibility complex class I (MHC-I) molecules to facilitate virus spreading. The Nef-induced downregulation of MHC-I molecules such as HLA-A requires the clathrin adaptor protein 1 (AP-1) complex. The cooperative interaction of Nef, AP-1, and the cytosolic tail (CT) of HLA-A leads to a redirection of HLA-A targeting from the trans-Golgi network (TGN) to lysosomes for degradation. Although the γ-adaptin subunit of AP-1 has two distinct isoforms (γ1 and γ2), which may form two AP-1 complex variants, so far, only the importance of AP-1γ1 in MHC-I downregulation by Nef has been investigated. Here, we report that the AP-1γ2 isoform also participates in this process. We found that AP-1γ2 forms a complex with Nef and HLA-A2_CT and that this interaction depends on the Y320 residue in HLA-A2_CT and Nef expression. Moreover, Nef targets AP-1γ1 and AP-1γ2 to different compartments in T cells, and the depletion of either AP-1 variant impairs the Nef-mediated reduction of total endogenous HLA-A levels and rescues HLA-A levels on the cell surface. Finally, immunofluorescence and immunoelectron microscopy analyses reveal that the depletion of γ2 in T cells compromises both the Nef-mediated retention of HLA-A molecules in the TGN and targeting to multivesicular bodies/late endosomes. Altogether, these results show that in addition to AP-1γ1, Nef also requires the AP-1γ2 variant for efficient MHC-I downregulation. IMPORTANCE HIV-1 Nef mediates evasion of the host immune system by inhibiting MHC-I surface presentation of viral antigens. To achieve this goal, Nef modifies the intracellular trafficking of MHC-I molecules in several ways. Despite being the subject of intense study, the molecular details underlying these modifications are not yet fully understood. Adaptor protein 1 (AP-1) plays an essential role in the Nef-mediated downregulation of MHC-I molecules such as HLA-A in different cell types. However, AP-1 has two functionally distinct variants composed of either γ1 or γ2 subunit isoforms. Because previous studies on the role of AP-1 in MHC-I downregulation by Nef focused on AP-1γ1, an important open question is the participation of AP-1γ2 in this process. Here, we show that AP-1γ2 is also essential for Nef-mediated depletion of surface HLA-A molecules in T cells. Our results indicate that Nef hijacks AP-1γ2 to modify HLA-A intracellular transport, redirecting these proteins to lysosomes for degradation.

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

Two Functional Variants of AP-1 Complexes Composed of either γ2 or γ1 Subunits Are Independently Required for Major Histocompatibility Complex Class I Downregulation by HIV-1 Nef

Tavares

Carvalho

Costa

et al. 2020

J Virol

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“…Sortilin levels are not increased in σ1B −/− brains 4 , 5 . γ1AP-1 levels are reduced in σ1B −/− synapses, but not in adipocytes, and AP-2 levels are only increased by 10% in σ1B −/− adipocytes 6 . Thus the changes in AP-1 and AP-2 dependent protein transport in σ1B −/− synapses are synapse specific and are thus novel molecular mechanisms of synaptic plasticity.…”

Section: Introductionmentioning

confidence: 79%

“…The increase in AP-2 CCV is a tissue and synapse specific secondary phenotype of AP-1/σ1B-deficiency. Regulation of CME is thus a mechanism of synaptic plasticity 4 , 6 . We describe the biochemical characterisation of the AP-1/σ1B knock-out induced synaptic CCV.…”

Section: Discussionmentioning

confidence: 99%

“…Differential AP-1/μ1A activation could play a role in the differential activation and thus different functions of γ2 and γ1 AP-1 complexes. In addition, the three μ1 isoforms are expected to be activated by different kinases 6 , 63 , 64 . Differential AP-2 activation could be achieved by specific targeting of kinases to the site of CME, e.g.…”

Section: Discussionmentioning

confidence: 99%

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Differential regulation of synaptic AP-2/clathrin vesicle uncoating in synaptic plasticity

Candiello

Mishra

Schmidt

et al. 2017

Sci Rep

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AP-1/σ1B-deficiency causes X-linked intellectual disability. AP-1/σ1B −/− mice have impaired synaptic vesicle recycling, fewer synaptic vesicles and enhanced endosome maturation mediated by AP-1/σ1A. Despite defects in synaptic vesicle recycling synapses contain two times more endocytic AP-2 clathrin-coated vesicles. We demonstrate increased formation of two classes of AP-2/clathrin coated vesicles. One which uncoats readily and a second with a stabilised clathrin coat. Coat stabilisation is mediated by three molecular mechanisms: reduced recruitment of Hsc70 and synaptojanin1 and enhanced μ2/AP-2 phosphorylation and activation. Stabilised AP-2 vesicles are enriched in the structural active zone proteins Git1 and stonin2 and synapses contain more Git1. Endocytosis of the synaptic vesicle exocytosis regulating Munc13 isoforms are differentially effected. Regulation of synaptic protein endocytosis by the differential stability of AP-2/clathrin coats is a novel molecular mechanism of synaptic plasticity.

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Hsc70 phosphorylation patterns and calmodulin regulate AP2 Clathrin-Coated-Vesicle life span for cell adhesion protein transport

Sengül,

Mishra,

Candiello

et al. 2024

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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γ2 and γ1AP-1 complexes: Different essential functions and regulatory mechanisms in clathrin-dependent protein sorting

Cited by 11 publications

References 70 publications

Two Functional Variants of AP-1 Complexes Composed of either γ2 or γ1 Subunits Are Independently Required for Major Histocompatibility Complex Class I Downregulation by HIV-1 Nef

Two Functional Variants of AP-1 Complexes Composed of either γ2 or γ1 Subunits Are Independently Required for Major Histocompatibility Complex Class I Downregulation by HIV-1 Nef

Differential regulation of synaptic AP-2/clathrin vesicle uncoating in synaptic plasticity

Hsc70 phosphorylation patterns and calmodulin regulate AP2 Clathrin-Coated-Vesicle life span for cell adhesion protein transport

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