Selective Export of HLA-F by Its Cytoplasmic Tail

Boyle, Louise H.; Gillingham, Alison K.; Munro, Sean; Trowsdale, John

doi:10.4049/jimmunol.176.11.6464

Cited by 78 publications

(92 citation statements)

References 52 publications

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“…Post-PLC, MHC I molecules are exported from the ER via a selective process, involving trafficking motifs in the HC cytoplasmic tails and Bap31, which facilitates recruitment into COP-II coated vesicles (31)(32)(33)(34)(35)(36). A bottleneck in the MHC I pathway appears to occur before the medial Golgi with the transport of suboptimally loaded MHC I molecules and PLC components blocked at this step (4,(37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway

Boyle

Hermann

Boname

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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106

153

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Tapasin is an integral component of the peptide-loading complex (PLC) important for efficient peptide loading onto MHC class I molecules. We investigated the function of the tapasin-related protein, TAPBPR. Like tapasin, TAPBPR is widely expressed, IFN-γ-inducible, and binds to MHC class I coupled with β2-microglobulin in the endoplasmic reticulum. In contrast to tapasin, TAPBPR does not bind ERp57 or calreticulin and is not an integral component of the PLC. β2-microglobulin is essential for the association between TAPBPR and MHC class I. However, the association between TAPBPR and MHC class I occurs in the absence of a functional PLC, suggesting peptide is not required. Expression of TAPBPR decreases the rate of MHC class I maturation through the secretory pathway and prolongs the association of MHC class I on the PLC. The TAPBPR: MHC class I complex trafficks through the Golgi apparatus, demonstrating a function of TAPBPR beyond the endoplasmic reticulum/ cis-Golgi. The identification of TAPBPR as an additional component of the MHC class I antigen-presentation pathway demonstrates that mechanisms controlling MHC class I expression remain incompletely understood.

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Section: Discussionmentioning

confidence: 99%

Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway

Boyle

Hermann

Boname

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

153

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“…Of note, C⌬12 and C⌬15 share the presence of a COOH-terminal valine. This configuration promotes ER export for several full and truncated membrane proteins (14,16,38,39). However, unlike C⌬12, C⌬15 was not able to convert to mature form, strongly suggesting that the COOH-terminal valine is very unlikely to be the sole discriminating factor for C⌬12 export from the ER.…”

Section: Influence Of Cooh-terminal Truncations On the Steady Statementioning

confidence: 99%

A Highly Conserved Motif at the COOH Terminus Dictates Endoplasmic Reticulum Exit and Cell Surface Expression of NKCC2

Zaarour

Demaretz

Defontaine

et al. 2009

Journal of Biological Chemistry

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Mutations in the apically located Na؉ -K ؉ -2Cl ؊ co-transporter, NKCC2, lead to type I Bartter syndrome, a life-threatening kidney disorder, yet the mechanisms underlying the regulation of mutated NKCC2 proteins in renal cells have not been investigated. Here, we identified a trihydrophobic motif in the distal COOH terminus of NKCC2 that was required for endoplasmic reticulum (ER) exit and surface expression of the cotransporter. Indeed, microscopic confocal imaging showed that a naturally occurring mutation depriving NKCC2 of its distal COOH-terminal region results in the absence of cell surface expression. Biotinylation assays revealed that lack of cell surface expression was associated with abolition of mature complexglycosylated NKCC2. Pulse-chase analysis demonstrated that the absence of mature protein was not caused by reduced synthesis or increased rates of degradation of mutant co-transporters. Co-immunolocalization experiments revealed that these mutants co-localized with the ER marker protein-disulfide isomerase, demonstrating that they are retained in the ER. Cell treatment with proteasome or lysosome inhibitors failed to restore the loss of complex-glycosylated NKCC2, further eliminating the possibility that mutant co-transporters were processed by the Golgi apparatus. Serial truncation of the NKCC2 COOH terminus, followed by site-directed mutagenesis, identified hydrophobic residues 1081 LLV 1083 as an ER exit signal necessary for maturation of NKCC2. Mutation of 1081 LLV 1083 to AAA within the context of the full-length protein prevented NKCC2 ER exit independently of the expression system. This trihydrophobic motif is highly conserved in the COOH-terminal tails of all members of the cation-chloride co-transporter family, and thus may function as a common motif mediating their transport from the ER to the cell surface. Taken together, these data are consistent with a model whereby naturally occurring premature terminations that interfere with the LLV motif compromise co-transporter surface delivery through defective trafficking.The Na-K-2Cl co-transporter, NKCC2, provides the major route for sodium/chloride transport across the apical plasma membrane of the thick ascending limb (TAL) 3 of the kidney (1). This co-transporter is critical for salt reabsorption, acid-base regulation, and divalent mineral cation metabolism (2). The prominent importance of NKCC2 in renal functions is evidenced by the effect of loop diuretics, which as pharmacologic inhibitors of NKCC2, are extensively used in the treatment of edematous states (2). Even more impressive, inactivating mutations of the NKCC2 gene in humans causes Bartter syndrome type 1 (BS1), a life-threatening renal tubular disorder for which the diagnosis is usually made in the antenatal-neonatal period, due to the presence of polyhydramnios, premature delivery, salt loss, hypokalemia, metabolic alkalosis, hypercalciuria, and nephrocalcinosis (3). Without appropriate treatment, patients with BS1 will not survive the early neonatal period (4). In congruen...

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“…To this regard, we recently demonstrated for the first time that WJ-MSC do express also other class Ib MHC molecules, namely HLA-E and HLA-F [45]: both are implicated in tolerogenic processes occurring at the foetomaternal interface, together with HLA-G [79][80][81]. Recent studies suggested additional functions for HLA-F other than antigen peptide loading [82,83]. Both HLA-E and HLA-F share a low genetic polymorphism (i.e.…”

Section: Recent Data On the Expression Of Relevant Immunomodulatory Mmentioning

confidence: 99%

Novel Immunomodulatory Markers Expressed by Human WJ-MSC: an Updated Review in Regenerative and Reparative Medicine

Rocca¹,

Corrao

Iacono

et al. 2012

TOTERMJ

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Mesenchymal (stromal) stem cells (MSC) are a broad class of stromal populations which are able to differentiate towards mature cell types, and do express molecules involved in immune modulation, tolerance induction and inflammation dampening. MSC can be virtually isolated from each adult organ, as well as from foetus-associated perinatal tissues. In particular, Wharton's jelly-derived MSC (WJ-MSC) bear all of these key properties, together with their ease of sourcing and lack of ethical issues.Cellular therapy is a key technique in regenerative medicine approaches, in particular for the treatment of diseases in which physiological processes of cellular repopulation are blocked by the underlying pathological conditions. Recent data enlightened the ability of administered cells to act also in a repopulation-independent fashion in target organs, since their peculiar immunomodulatory and anti-inflammatory features may favor organ self-repair by reactivating local progenitors by both cell-mediated or paracrine mechanisms. Translating classical regenerative medicine to "reparative medicine" or "support medicine" should represent a further therapeutic strategy independent from the differentiation capacity of MSC populations.Recent data further highlighted that WJ-MSC outperform BM-MSC (which are now being applied clinically) both in terms of immune modulation and lack of tumorigenesis (or tumor-promoting activities) in vivo. Starting from these premises, this paper analyzes the recent data on the biology of WJ-MSC, considering the role of both naïve and differentiated cells in immune modulation. In particular, the role of tolerance promoting pathways via non-classical B7 costimulators or class Ib MHC molecules are examined. In addition, we also analyzed the interconnections with other mechanicistic pathways (as those driven by matrix degrading metalloproteinases) in immune modulation. Our observations strongly support the notion that WJ-MSC may constitute a new tool in regenerative and reparative medicine applications.

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Selective Export of HLA-F by Its Cytoplasmic Tail

Cited by 78 publications

References 52 publications

Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway

Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway

A Highly Conserved Motif at the COOH Terminus Dictates Endoplasmic Reticulum Exit and Cell Surface Expression of NKCC2

Novel Immunomodulatory Markers Expressed by Human WJ-MSC: an Updated Review in Regenerative and Reparative Medicine

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