The RELT Family of Proteins: An Increasing Awareness of Their Importance for Cancer, the Immune System, and Development

Abstract

This review highlights Receptor Expressed in Lymphoid Tissues (RELT), a Tumor Necrosis Factor Superfamily member, and its two paralogs, RELL1 and RELL2. Collectively, these three proteins are referred to as RELTfms and have gained much interest in recent years due to their association with cancer and other human diseases. A thorough knowledge of their physiological functions, including the ligand for RELT, is lacking, yet emerging evidence implicates RELTfms in a variety of processes including cytokine signaling and pathways that either promote cell death or survival. T cells from mice lacking RELT exhibit increased responses against tumors and increased inflammatory cytokine production, and multiple lines of evidence indicate that RELT may promote an immunosuppressive environment for tumors. The relationship of individual RELTfms in different cancers is not universal however, as evidence indicates that individual RELTfms may be risk factors in certain cancers yet appear to be protective in other cancers. RELTfms are important for a variety of additional processes related to human health including microbial pathogenesis, inflammation, behavior, reproduction, and development. All three proteins have been strongly conserved in all vertebrates, and this review aims to provide a clearer understanding of the current knowledge regarding these interesting proteins.

Keywords: RELL1; RELL2; RELT; TNFRSF; apoptosis; cancer; cytokine signaling; immune cells; inflammation; interferon.

Figure 1

Model for signaling by the RELT family members (RELTfms), RELT, RELL1, and RELL2. Note: RELTfms bind each other, yet it is not yet known if they function as trimers, and it is not known whether RELT binds to an unidentified ligand. The possibility that RELL1 and RELL2 function independently of RELT cannot be excluded. Protein binding partners of RELT that also bind RELL1 or RELL2 (e.g., PLSCR1 [25], MDFIC [23], OXSR1 [9], and SPAK [27,28]) are only shown in color for RELT for simplicity. Unique binding partners to either RELL1 or RELL2 are shown in color. Similarly, the activation of p38 by RELTfms [21,27] is only shown in color for RELT. Activation of NF-κB has been demonstrated for both RELL1 [28] and RELT [7,29]. The activation of the JNK pathway has only been shown for RELT [27]. Not shown are additional localizations reported for RELTfms, including intracellular vesicles [9,25] and the nucleus for RELT, as predicted by the Human Protein Atlas (HPA). The HPA predicts that RELL1 is located at both the plasma membrane and is associated with microtubules, while it predicts that RELL2 localizes to intracellular vesicles. Please note that only known activities of RELTfm proteins are shown. Not shown are activities reported for circular RNA molecules expressed from the RELL1 gene, including pro-inflammatory functions [18] and the ability to both promote apoptosis and inhibit autophagy [19].