Crosstalk between vault RNAs and innate immunity

Abstract

Purpose: Vault (vt) RNAs are noncoding (nc) RNAs transcribed by RNA polymerase III (RNA Pol III) with 5'-triphosphate (5'-PPP) termini that play significant roles and are recognized by innate immune sensors, including retinoic acid-inducible protein 1 (RIG-I). In addition, vtRNAs adopt secondary structures that can be targets of interferon-inducible protein kinase R (PKR) and the oligoadenylate synthetase (OAS)/RNase L system, both of which are important for activating antiviral defenses. However, changes in the expression of vtRNAs have been associated with pathological processes that activate proinflammatory pathways, which influence cellular events such as differentiation, aging, autophagy, apoptosis, and drug resistance in cancer cells.

Results: In this review, we summarized the biology of vtRNAs and focused on their interactions with the innate immune system. These findings provide insights into the diverse roles of vtRNAs and their correlation with various cellular processes to improve our understanding of their biological functions.

Keywords: Innate immunity; RIG-I and PKR; Vault RNAs.

Fig. 1

The human vault RNAs biogenesis. The four vtRNAs are encoded on two loci on chromosome 5. vtRNA 1-1, vtRNA 1-2, vtRNA 1-3 encode on locus 5q31.3, while vtRNA 2-1 is encoded on locus 5q31. All vtRNAs are expressed by RNA polymerase III [–59]. vtRNAs can be associated with vault particles which are involved in different cellular processes [58, 64]. vtRNAs may remain unprocessed and protected from methylation by the SRSF2 protein. Full-length vtRNAs can participate in several cellular processes [73, 74]. Additionally, vtRNAs may undergo fragmentation through m5C methylation at position C69 by NSUN2 protein. This methylation facilitates the fragmentation into small vault RNAs (svtRNAs) by DICER. Some svtRNAs can be loaded into AGO2, regulating posttranscriptional gene silencing [65, 73]

Fig. 2

Interactions of innate immune proteins with vtRNA 2-1. PKR binds to vtRNA 2-1 at positions 40–42 nt, resulting in the unphosphorylated and inactivated PKR [84]. The essential nucleotides for PKR interactions are encircled in blue. OAS1 can bind to the apical stem-loop region (40–50 nt) of vtRNA 2-1. However, the details of this interaction remain unknown [89]. The critical nucleotides for OAS1 recognition are encircled in red. B) vtRNA 2-1 downregulation (green arrow) allows the activation of PKR through dimerization and phosphorylation and promotes the activation of NF-κB increasing proliferation and inflammatory response [84, 85]

Fig. 3

Vault RNA 1-1 and Vault particles play a crucial role in the regulation of apoptosis and autophagy. The stem-loop structure in the apical region of vtRNA 1-1 enhances resistance to apoptosis by modulating the PI3K/Akt and ERK1/2 MAPK signaling pathways, with critical nucleotides for apoptosis resistance encircled in blue [87, 127]. Additionally, vtRNA 1-1 inhibits autophagy by preventing p62 oligomerization, and the relevant nucleotides for this proposed role are encircled in red [138, 143]. Moreover, vault particles can interact with SQSTM1/p62, contributing to the enhancement of the vault-phagy process [141]