Table 2.

Regulation of NKG2D ligands

Transcriptional regulation Proliferative conditions induce expression of Raet1 family genes and the MICA and ULBP2 genes. E2F transcription factors transactivate Raet1 family genes [55]. Heat shock and the heat shock factor 1 (HSF1) regulate the MICA and MICB genes [56,57]. The p53 transcription factor amplifies transcription of ULBP1 and ULBP2 genes [58,59]. NF-κB and Sp family transcription factors regulate the transcriptional activation of human NKG2D ligands [60,61]. The ATF4 transcription factor induces ULBP1 gene expression [62].

Regulation at the mRNA Level The DNA damage response (DDR) pathway is an important mode of regulation of NKG2D ligands in both mouse and human cells and appears to act largely post-transcriptionally [32,63,64]. AID deregulation in Abelson murine leukemia virus-infected cells induced the DDR and the expression of NKG2D ligands [65]. The HIV Vpr protein activates the ATR kinase and the DDR leading to the expression of NKG2D ligands [66]. The HIV Vif protein degrades the antiviral host protein APOBEC3G, preventing the deamination of cytosine residues, the DDR and the expression of NKG2D ligands [67]. Many different microRNAs have been implicated in NKG2D ligands regulation, including miR-17-5p, miR-20a, miR-34a, miR-34c, miR-93, miR-106b, miR-373, and miR-520 [68]. PI3K signaling was implicated in the induction of RAE-1 [69]. The oncogene RAS induces the expression of RAE-1α and RAE- 1β in mouse cells as well as ULBP1-3 in human cells [70]. The adenovirus E1A oncogene protein induces Raet1 mRNAs and the RAE-1 protein [71]. The RNA-binding protein RBM4 supports ULBP1 expression by facilitating proper splicing of the first two exons of the primary transcript [62].

Regulation at the Protein Level UV irradiation or heat shock reduces the poly-ubiquitination of MULT1 protein resulting in its stabilization and induction at the cell surface. MULT1 degradation was in part mediated by two ubiquitin ligases, MARCH4 and MARCH9, which regulate turnover of the ligand cell-surface induction [72,73].