Cooperative Binding of the Class I Major Histocompatibility Complex Cytoplasmic Domain and Human Immunodeficiency Virus Type 1 Nef to the Endosomal AP-1 Complex via Its μ Subunit

Aslan

Journal of Cell Science

et al. 2017

Vertebrate proteins that fulfill multiple and seemingly disparate functions are increasingly recognized as vital solutions to maintaining homeostasis in the face of the complex cell and tissue physiology of higher metazoans. However, the molecular adaptations that underpin this increased functionality remain elusive. In this Commentary, we review the PACS proteins -which first appeared in lower metazoans as protein traffic modulators and evolved in vertebrates to integrate cytoplasmic protein traffic and interorganellar communication with nuclear gene expression -as examples of protein adaptation 'caught in the act'. Vertebrate PACS-1 and PACS-2 increased their functional density and roles as metabolic switches by acquiring phosphorylation sites and nuclear trafficking signals within disordered regions of the proteins. These findings illustrate one mechanism by which vertebrates accommodate their complex cell physiology with a limited set of proteins. We will also highlight how pathogenic viruses exploit the PACS sorting pathways as well as recent studies on PACS genes with mutations or altered expression that result in diverse diseases. These discoveries suggest that investigation of the evolving PACS protein family provides a rich opportunity for insight into vertebrate cell and organ homeostasis.

Section: Introductionmentioning

confidence: 99%

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

Aslan

Journal of Cell Science

et al. 2017

“…In contrast to the signalling pathway, the stoichiometric mode is independent of PI3K signalling and involves the diversion of newly synthesized MHC-I molecules in the TGN to lysosomal compartments that is mediated by the M20 residue on Nef /AP-1 and the process is clathrin dependent [8,11,63]. The stoichiometric pathway is initiated when Nef binds to the tyrosine residue at position 320 on the cytoplasmic tail of the MHC-I molecule via its acidic cluster (EEEE 65 ) and proline rich repeat (PXXP [72][73][74][75] ) [11,33,64]. As highlighted above the Nef-MHC-I complex creates a hydrophobic region which enables the µ1 subunit of clatherin to bind [11,65].…”

Section: Stoichiometric Modementioning

confidence: 99%

“…The SFK/ZAP-70/PI3K complex can induce tyrosine kinase signalling and this can increase the rate of endocytosis of cell surface MHC-I proteins from the cell surface [4,30,58]. Once the MHC-I proteins are internalized they can be sequestered within the paranuclear region which requires the M 20 and EEEE 65 domains of Nef interacting with PACS-1 and the AP-1 protein [11,30]. The activation of PI3K triggers the clathrin-independent, GTPase ADP ribosylation factor 6 (ARF6)-dependent endocytosis of MHC-I molecules [8,30].…”

Section: Signalling Modementioning

confidence: 99%

“…The pathway involves two domains on Nef, the EEEE 65 acidic cluster and the PXXP 75 SH3 domain binding site, which are both located at the N-terminus of the protein [30,58,61]. Following viral infection Nef can downregulate MHC-I by activating an endocytic program that requires the Nef 's acidic cluster (EEEE [62][63][64][65] ) to bind to the endosomal sorting protein PACS-2 and this targets the Nef to a paranuclear region [30,61]. This change to its cellular localization facilitates the interaction of the Nef PXXP 75 SH3 binding domain to form a multiprotein complex involving Src Family kinases (SFK)/zeta associated protein kinase 70 (ZAP70)/ phosphatidylinositol kinase 3 (PI3K) i.e.…”

Section: Signalling Modementioning

confidence: 99%

See 1 more Smart Citation

The Role of the Nef Protein in MHC-I Downregulation and Viral Immune Evasion by HIV-1

Elliott¹,

Hoyne²

2015

J Clin Cell Immunol

The Nef protein is a major determinant of pathogenicity caused by the human immunodeficiency virus (HIV) and is encoded by the nef gene within the genomes of primate lentiviruses HIV-1, HIV-2 and simian immunodeficiency virus (SIV). The HIV Nef protein subverts the intracellular membrane traffic to mediate endocytosis of a number of cell surface receptors to accelerate their degradation. In this review we will examine how the multifunctional Nef can mediate down regulation of the Major histocompatibility Complex (MHC) I complex proteins from the surface of infected cells as a means of immune evasion by HIV. By selectively downregulating MHC-I HLA-A and HLA-B haplotypes, while maintaining the expression of HLA-C, HLA-E and HLA-G the HIV virus is able to avoid recognition by both the NK and cytotoxic CD8 + T cell effector responses. This protects the virus from cell lysis and enables it to hide from the cell-mediated immune system.

The Journal of Immunology

“…Current models suggest that Nef retains MHC-I in the trans-Golgi network (TGN) by forming a complex with AP-1 in a mechanism not related to the Nef dileucine motif-AP-1 interaction. The MHC-I-Nef-AP-1 complex is not sorted to the plasma membrane, instead it follows an endosomal-degradation pathway (19,24,25).…”

mentioning

confidence: 99%

Two Sorting Motifs, a Ubiquitination Motif and a Tyrosine Motif, Are Involved in HIV-1 and Simian Immunodeficiency Virus Nef-Mediated Receptor Endocytosis

Cai

Zhang

Sinko

et al. 2011

HIV-1 and SIV Nef proteins downregulate cell surface CD4 and MHC class I (MHC-I) molecules of infected cells, which are necessary for efficient viral replication and pathogenicity. We previously reported that K144 in HIV-1 Nef is di-ubiquitinated, and K144R substitution impairs Nef-mediated CD4 downregulation. In this report, we extend the role of ubiquitination at this lysine residue from Nef-mediated CD4 downregulation to Nef-mediated MHC-I downregulation and from HIV Nef to SIV Nef. All HIV-1 Nef mutants that contain K144R substitution are inactive in MHC-I downregulation. Tested MHC-I alleles include HLA-ABC endogenously expressed and HLA-A2 exogenously expressed in Jurkat T cells. CD4 downregulation by SIV Nef involves K176 that aligns with K144 in HIV-1 Nef, as well as an N-terminal tyrosine motif Y28Y39 not present in HIV-1 Nef. Dual mutation at K176 and Y28Y39 completely impaired SIV Nef-mediated CD4 and MHC-I downregulation, whereas a single mutation at K176 or Y28Y39 did not. The involvement of tyrosine motif in SIV Nef-mediated CD4 and MHC-I downregulation prompted us to investigate a putative tyrosine motif (Y202Y/F203) in HIV-1 Nef that is conserved among HIV-1 species. Single mutation at the tyrosine motif Y202F203 in HIV-1 Nef (NA7) greatly impaired Nef-mediated CD4 downregulation, which is similar to what we observed previously with the single mutation at lysine K144. Thus, our study demonstrated that Nef-mediated receptor endocytosis involves the ubiquitination motif and tyrosine motif.