Abstract
Natural Killer Lytic-Associated Molecule (NKLAM), also designated RNF19B, is a unique member of a small family of E3 ubiquitin ligases. This 14-member group of ligases has a characteristic cysteine-rich RING-IBR-RING (RBR) domain that mediates the ubiquitination of multiple substrates. The consequence of substrate ubiquitination varies, depending on the type of ubiquitin linkages formed. The most widely studied effect of ubiquitination of proteins is proteasome-mediated substrate degradation; however, ubiquitination can also alter protein localization and function. Since its discovery in 1999, much has been deciphered about the role of NKLAM in innate immune responses. We have discerned that NKLAM has an integral function in both natural killer (NK) cells and macrophages in vitro and in vivo. NKLAM expression is required for each of these cell types to mediate maximal killing activity and cytokine production. However, much remains to be determined. In this review, we summarize what has been learned about NKLAM expression, structure and function, and discuss new directions for investigation. We hope that this will stimulate interest in further exploration of NKLAM.
Highlights
TO Natural Killer Lytic-Associated Molecule (NKLAM)Discovery of NKLAMStudies were initiated to identify new genes and gene products associated with cytokine-enhanced natural killer (NK) anti-tumor cytotoxic activity
Kinetic analysis determined that NKLAM mRNA levels peak 4–6 h after IFNβ stimulation of NK cells; NKLAM levels are strongly induced by interleukin (IL)-2, peaking
Mouse macrophage cell lines RAW 264.7 and J774A.1 were stimulated with TLR4 agonist lipopolysaccharide (LPS), the combination of LPS plus IFNγ, Escherichia coli, or Staphylococcus aureus and NKLAM protein expression was assessed over time
Summary
Studies were initiated to identify new genes and gene products associated with cytokine-enhanced natural killer (NK) anti-tumor cytotoxic activity. For these experiments, we used the human NK clone NK3.3, which had been generated previously (Kornbluth et al, 1982). A cDNA library from interferon beta (IFNβ) stimulated NK3.3 cells was made and differential screening was performed to compare expression in unstimulated cells. From this analysis, 56 IFNβ-upregulated genes were identified; 46 were novel at the time. Kinetic analysis determined that NKLAM mRNA levels peak 4–6 h after IFNβ stimulation of NK cells; NKLAM levels are strongly induced by interleukin (IL)-2, peaking
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