Table 1.
Mechanisms regulating NKG2D ligand expression in steady state conditions and in response to stimuli.
| Regulatory level | Condition/stimuli | Pathway/molecule | Ligand modulation | Cell type | NK cell functions | Reference |
|---|---|---|---|---|---|---|
| TRANSCRIPTIONAL | ||||||
| Ionizing radiation, cisplatin, and 5-FU | DDR | ↑ MICA, ULBP1–3 ↑ RAE-1, MULT1 |
HFF; C1, C2 cell lines | ↑ Cytotoxicity | (16) | |
| Doxorubicin and melphalan | DDR/E2F1 | ↑ MICA | Multiple myeloma | ↑ Cytotoxicity ↑ IFNγ |
(17, 18) | |
| Activation/proliferation | NF-κB NF-κB E2F1 |
↑ MICA ↑ MICA ↑ RAE-1ε |
T cells T cells Primary fibroblasts, embrionic brain cells |
n.d. ↑ Cytotoxicity ↑ Cytotoxicity |
(9) (19) (20) |
|
| Ara-C | STING/TBK/IRF3 | ↑ RAE-1 | B cell lymphoma | ↑ Cytotoxicity | (21) | |
| RITA Vincristine |
p53 p53 p53 |
↑ ULBP1, ULBP2 ↑ ULBP2 ↑ ULBP1 |
Cancer cell lines Cancer cell lines Multiple myeloma |
↑ Cytotoxicity ↑ IFNγ ↑ Cytotoxicity ↑ Cytotoxicity |
(22) (23) (24) |
|
| Heat shock response | HSF1 | ↑ MICA, MICB | Cancer cell lines Multiple myeloma |
n.d. ↑ Cytotoxicity |
(25) (26) |
|
| ER-induced stress | CHOP | ↑ ULBP1 ↑ MULT1 |
Intestinal epithelial cells | ↑ Cytotoxicity | (27) | |
| Steady state | STAT3 | ↑ MICA | Colonrectal cancer Multiple myeloma |
↑ Cytotoxicity ↑ IFNγ ↑ Cytotoxicity |
(28) (29) |
|
| Steady state | IKZE1/3, IRF4 | ↑ MICA | Multiple myeloma | ↑ Cytotoxicity | (30, 31) | |
| RNA SPLICING | ||||||
| Steady state | RBM4 | ↓ ULBP1 | HAP1 cell line | n.d. | (32) | |
| POSTTRANSCRIPTIONAL | ||||||
| Steady state | AUF1 | ↓ ULBP2, MICB | Epithelial cells | n.d. | (33) | |
| Steady state | miR34a, c miR-519a-3p miR-93 miR-20a |
↓ ULBP2 ↓ MICA, ULBP2 ↓ MICA, MICB, ULBP3 ↓ MICA, MICB, ULBP2 |
Melanoma cell lines Mammary epithelial cell line Glioma cell lines Cancer cell lines |
↓ Cytotoxicity ↓ Cytotoxicity ↓ Cytotoxicity ↓ Cytotoxicity |
(34) (35) (36) (37, 38) |
|
| IFNγ | miR-520b | ↓ MICA | Cancer cell lines | n.d. | (39) | |
| HCMV, KSHV, and EBV | miR-UL112; miRK12-7; and miR-BART2-5 |
↓ MICB | Infected HFF cells; cancer cell lines | ↓ Cytotoxicity | (40, 41) | |
| JCV | miR-J1-3p | ↓ ULBP3 | Infected cancer cell lines | ↓ Cytotoxicity | (42) | |
| Posttranslational | ||||||
| Steady state | Ubiquitination | ↓ MULT1 | Cancer cell lines | n.d. | (43) | |
| KSHV | K5 ubiquitin ligase | ↓ MICA | Cancer cell lines | ↓ Cytotoxicity | (44) | |
| Histamine | Ubiquitination | ↓ MICA | Monocytic leukemia | ↓ Cytotoxicity | (45) | |
| Steady state | ADAMs and MMPs (protease-mediated shedding) | ↓ MICA, MICB, ULBP2 | Cancer cell lines | ↓ Cytotoxicity n.d. |
(46–48) (49–51) |
|
↓ Decrease; ↑ increase; HFF, human foreskin fibroblasts; HCMV, human cytomegalovirus; EBV, Epstein–Barr virus; KSHV, Kaposi’s sarcoma-associated herpes virus; JCV, human polyoma virus JC; ADAM, a disintegrin and metalloprotease; MMP, matrix metalloprotease; n.d., not done; CHOP, C/EBP homology protein.
Ref. (48) provides an ample overview on protease-mediated shedding of NKG2D ligands.