N-Glycosylation of Asparagine 8 Regulates Surface Expression of Major Histocompatibility Complex Class I Chain-related Protein A (MICA) Alleles Dependent on Threonine 24

Mellergaard, Maiken; Skovbakke, Sarah Line; Schneider, Christine L.; Lauridsen, Felicia Kathrine Bratt; Andresen, Lars Ole; Jensen, Hans Grinsted; Skov, Søren

doi:10.1074/jbc.m114.573238

Cited by 28 publications

(22 citation statements)

References 58 publications

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“…However, the mechanisms behind ULBP4 translocation remain elusive. Some studies have demonstrated that N-linked glycosylation regulated the translocation of MICA/B from the cytoplasm to the membrane (57,58). However, we have shown that tunicamycin, a selective inhibitor of N-linked glycosylation, did not abolish HCQ-induced ULBP4 expression (data not shown).…”

Section: Discussioncontrasting

confidence: 60%

Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy

Han

Zhao

Lin

et al. 2017

International Journal of Oncology

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Hydroxychloroquine (HCQ) is the only autophagy inhibitor in clinical use and it has shown great potential in treating chronic myeloid leukemia (CML). By inhibiting autophagy, HCQ enhances the anti-CML efficiency of chemotherapy. In the present study, we demonstrated that HCQ sensitized CML cells to Vγ9Vδ2 T cell-mediated lysis. HCQ inhibited autophagy in CML cells, but the sensitizing effects of HCQ were autophagy-independent. Since the sensitization was not mimicked by ATG7 knockdown and even occurred in the absence of ATG7. We revealed that in a time-dependent manner HCQ induced the expression of NKG2D ligand ULBP4 on the surface of CML cells. This marks the leukemia cell for recognition by Vγ9Vδ2 T cells. Blocking the interaction of NKG2D with its ligands deleted the sensitizing effects of HCQ. In addition, we showed that HCQ did not affect the synthesis or degradation of ULBP4, but induced the translocation of ULBP4 from the cytoplasm to the cell membrane. Our results uncovered a previously unknown mechanism for HCQ in CML treatment that underlines the ability of HCQ to modulate the immune visibility of CML cells, and pave the way to the development of new combination treatments with HCQ and Vγ9Vδ2 T cells.

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Section: Discussioncontrasting

confidence: 60%

Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy

Han

Zhao

Lin

et al. 2017

International Journal of Oncology

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“…Indeed, it is wellestablished that certain MICA alleles/amino acids affect its binding affinity for NKG2D (for review, see Carapito and Bahram 18 ; for an example, see Mellergaard et al 41 ). Furthermore, and in accordance with a rather restricted expression pattern for the MICA glycoprotein, it is perhaps not surprising that MICA mismatches are associated with limited (and not extensive; ie, multiorgan) chronic GVHD (supplemental Table 3).…”

Section: Discussionmentioning

confidence: 99%

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

Carapito

Jung

Kwemou

et al. 2016

Blood

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“…Thus, MICA*A5.1 carriers may have an aberrant immunological surveillance by NK and T cells [9,52]. Furthermore, N-glycosylation requirement for cell trafficking of MICA*A5.1 is also different: there is an alanine residue at position 24 (a1 domain) in MICA*A5.1, instead of threonine; Thr 24 N-glycosylation directly regulates MICA surface expression and, therefore, regulation of the expression of MICA*A5.1 allele is not affected by changes in N-glycosylation [53]. MICA*A5.1 is not released from cells by proteolytic shedding due to the lack of the two cysteines required, but rather as a membrane anchored full-length molecule in exosomes [50,54].…”

Section: Discussionmentioning

confidence: 99%

MICAA4 protects against ulcerative colitis, whereas MICAA5.1 is associated with abscess formation and age of onset

Martínez-Chamorro

Moreno

Gómez‐García

et al. 2016

Clinical and Experimental Immunology

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SummaryUlcerative colitis (UC) is one of the two major forms of inflammatory bowel disease, the aetiology of which remains unknown. Several studies have demonstrated the genetic basis of disease, identifying more than 130 susceptibility loci. The major histocompatibility complex class I chainrelated gene A (MICA) is a useful candidate to be involved in UC pathogenesis, because it could be important in recognizing the integrity of the epithelial cell and its response to stress. The aim of this study was to analyse the relationship between polymorphisms in the transmembrane domain of MICA and susceptibility to develop UC. A total of 340 patients with UC and 636 healthy controls were genotyped for MICA transmembrane polymorphism using a polymerase chain reaction (PCR) combined with fluorescent technology. Different MICA alleles were determined depending on the PCR product size. The allele MICA*A4 was less frequent in patients than in controls (P 5 0Á003; OR 5 0Á643), and this protective role is higher when it forms haplotype with B*27 (P 5 0Á002; OR 5 0Á294). The haplotype HLA-B*52/MICA*A6 was also associated with UC [P 5 0Á001; odds ratio (OR) 5 2Á914]. No other alleles, genotypes or haplotypes were related with UC risk. Moreover, MICA*A5.1 is associated independently with abscesses (P 5 0Á002; OR 5 3Á096) and its frequency is lower in patients diagnosed between ages 17 and 40 years (P 5 0Á007; OR 5 0Á633), meaning an extreme age on onset. No association with location, extra-intestinal manifestations or need for surgery was found.

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N-Glycosylation of Asparagine 8 Regulates Surface Expression of Major Histocompatibility Complex Class I Chain-related Protein A (MICA) Alleles Dependent on Threonine 24

Cited by 28 publications

References 58 publications

Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy

Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

MICAA4 protects against ulcerative colitis, whereas MICAA5.1 is associated with abscess formation and age of onset

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N-Glycosylation of Asparagine 8 Regulates Surface Expression of Major Histocompatibility Complex Class I Chain-related Protein A (MICA) Alleles Dependent on Threonine 24

Cited by 28 publications

References 58 publications

Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy

Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

MICA*A4 protects against ulcerative colitis, whereas MICA*A5.1 is associated with abscess formation and age of onset

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MICAA4 protects against ulcerative colitis, whereas MICAA5.1 is associated with abscess formation and age of onset