RNASEL

Fig1. Structure of the RNase L. (Catherine Bisbal, 2007)

What is RNASEL protein?

RNASEL gene (ribonuclease L) is a protein coding gene which situated on the long arm of chromosome 1 at locus 1q25. It functions as an endoribonuclease, which means it is capable of cleaving single-stranded RNA (ssRNA). The activation of RNASEL is a critical component of the interferon-mediated antiviral response. When cells are exposed to interferon (IFN) and viral infections, RNASEL is activated, leading to the degradation of viral RNA and cellular RNA, which can inhibit viral replication and induce cell apoptosis. In addition to its antiviral role, RNASEL has been implicated in various other biological processes, including the regulation of mRNA turnover, cell proliferation, apoptosis, and autophagy. The RNASEL protein is consisted of 741 amino acids and RNASEL molecular weight is approximately 83.5 kDa.

What is the function of RNASEL protein?

RNASEL is activated in response to viral infections, leading to the degradation of both viral and cellular single-stranded RNA. Activated RNASEL can induce programmed cell death (apoptosis) in virus-infected cells, thereby limiting the virus's ability to replicate and propagate. RNASEL contributes to the regulation of mRNA stability and turnover, which can affect the expression of various genes. RNASEL has been implicated in the regulation of cell proliferation and differentiation, with its activity potentially influencing cell cycle progression and cell fate decisions. RNASEL can interact with components of the cellular cytoskeleton, which may be important for maintaining the cellular barrier to viral entry and for other cellular functions.

RNASEL Related Signaling Pathway

The 2-5A/RNase L pathway is the main activation pathway of RNASEL. When cells detect double-stranded RNA (dsRNA), 2'-5' -oligoadenylate synthetase (OAS) catalyzes the synthesis of 2'-5' -oligoadenylate (2-5A), a small molecule that activates RNASEL, giving it nuclease activity that degrades single-stranded RNA (including viral RNA). RNASEL is part of the interferon signaling pathway, and its activation enhances the cell's defense against viruses. By binding to its receptor, interferon activates the JAK-STAT signaling pathway, inducing the expression of the OAS gene, which in turn activates RNASEL in the presence of dsRNA. RNASEL is involved in the cellular innate immune response to limit viral replication by degrading viral RNA. It is also involved in regulating the activity of other innate immune molecules, such as Toll-like receptors (TLRs) and RIG-I receptors (RLRs). In the cytoplasm, RNASEL can act synergistically with the cGAS-STING pathway to activate downstream inflammatory and immune responses in response to DNA in the cytoplasm.

RNASEL Related Diseases

In terms of the immune system, ribonucnase L (RNase L) encoded by the RNASEL gene is an important antiviral protein involved in the 2-5A-dependent RNA degradation pathway, and its abnormality may affect the defense ability against viruses. In terms of tumor development, mutations in the RNASEL gene are significantly associated with Hereditary Prostate Cancer (HPC), particularly type I hereditary prostate cancer (HPC1), which is a predominately inherited form of the disease associated with early-onset, aggressive prostate cancer. The RNASEL gene is also associated with Aicardi-Goutieresyndrome (AGS), a genetic disorder characterized by neurodegeneration and immunoinflammation caused by overactivation of the RNASEL gene.

Bioapplications of RNASEL

RNASEL plays a central role in interferon-mediated antiviral responses, and its activation degrades viral RNA and inhibits viral replication. Therefore, RNASEL agonists or stabilizers may act as agents for antiviral therapy. Research on the chemical regulation of RNASEL has facilitated the development of novel small molecule drugs, such as RNASEL inhibitors screened by fragm-based drug development methods (FBDD), which may be used to treat diseases associated with over-activation of RNASEL. The expression level or activity of RNASEL may serve as a biomarker for certain disease states, which may be helpful in the diagnosis and prognosis assessment of the disease. The function of RNASEL may influence the safety and efficacy of cell therapy, especially in CAR-T cell therapy, and the regulation of RNASEL's activity may help optimize the therapeutic effect.

Case Study 1: Daniel F R Boehmer, 2021

Cytoplasmic double-stranded RNA is sensed by RIG-I-like receptors (RLRs), leading to induction of type I interferons (IFN-Is), proinflammatory cytokines, and apoptosis. Here, researchers elucidate signaling mechanisms that lead to cytokine secretion and cell death induction upon stimulation with the bona fide RIG-I ligand 5'-triphosphate RNA (3p-RNA) in tumor cells. They show that both outcomes are mediated by dsRNA-receptor families with RLR being essential for cytokine production and IFN-I-mediated priming of effector pathways but not for apoptosis. Affinity purification followed by mass spectrometry and subsequent functional analysis revealed that 3p-RNA bound and activated oligoadenylate synthetase 1 and RNase L. RNase L-deficient cells were profoundly impaired in their ability to undergo apoptosis. Mechanistically, the concerted action of translational arrest triggered by RNase L and up-regulation of NOXA was needed to deplete the antiapoptotic MCL-1 to cause intrinsic apoptosis.

Fig1. rRNA integrity analysis of total RNA isolated from 1205Lu DDX58−/− cells using RNA BioAnalyzer.

Fig2. Flow cytometric analysis of viability of WT or RNase L–deficient B16F10 cells 48 hours after transfection.

Case Study 2: James M Burke, 2020

Stress granules (SGs) are ribonucleoprotein (RNP) assemblies that form in eukaryotic cells as a result of limited translation in response to stress. SGs form during viral infection and are thought to promote the antiviral response because many viruses encode inhibitors of SG assembly. However, the antiviral endoribonuclease RNase L also alters SG formation, whereby only small punctate SG-like bodies that we term RNase L-dependent bodies (RLBs) form during RNase L activation. How RLBs relate to SGs and their mode of biogenesis is unknown. Herein, using immunofluorescence, live-cell imaging, and MS-based analyses, researchers demonstrate that RLBs represent a unique RNP granule with a protein and RNA composition distinct from that of SGs in response to dsRNA lipofection in human cells. RLBs are also generated independently of SGs and the canonical dsRNA-induced SG biogenesis pathway.

Fig3. Western blotting analysis of PKR and RNase L.

Fig4. Immunoblot analysis for RNase L in WT and eIF2α–S51A MEF cell lines transduced with RNase L–encoding lentivirus.

RNASEL has several biochemical functions, for example, ATP binding,RNA binding,endoribonuclease activity. Some of the functions are cooperated with other proteins, some of the functions could acted by RNASEL itself. We selected most functions RNASEL had, and list some proteins which have the same functions with RNASEL. You can find most of the proteins on our site.

RNASEL has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with RNASEL here. Most of them are supplied by our site. Hope this information will be useful for your research of RNASEL.

IQGAP1;KIF23