SLIRP: an anomalous factotum on nuclear signaling
SLIRP (SRA stem-loop interacting RNA binding protein) was firstly identified in 2006 and found to bind to a functional substructure of SRA called STR7. Steroid receptor RNA activator (SRA), the only known RNA coactivator, augments transactivation by nuclear receptors (NURs). SLIRP is expressed in normal and tumor tissues, contains an RNA recognition motif (RRM), represses NUR transactivation in a SRA- and RRM-dependent manner, augments the effect of Tamoxifen and modulates association of SRC-1 with SRA. SHARP, another RRM-containing corepressor, also binds STR7 augmenting repression with SLIRP. SLIRP colocalizes with SKIP, another NUR coregulator, and reduces SKIP-potentiated NUR signaling. SLIRP also modulates NUR transactivation, suggest it may regulate mitochondrial function, and provide mechanistic insight into interactions between SRA, SLIRP, SRC-1 and NCoR.
SLIRP and mitochondrial homeostasis
The majority of the endogenous SLIRP resides in the mitochondria. SLIRP silencing with RNAi results in destabilization of Oxidative Phoshorylation complexes and a marked loss of OxPhos enzymatic activity. Moreover, we show that SLIRP plays an essential role in maintaining mitochondrial-localized mRNA transcripts that encode OxPhos protein subunits. SLIRP exists in a high-molecular-weight complex, and it coimmunoprecipitates with LRPPRC. Mutations in LRPPRC are responsible for the French Canadian variant of Leigh syndrome, a neurodegenerative disorder caused by a tissue-specific deficiency in cytochrome c oxidase (COX). Knockdown of LRPPRC produces a generalized assembly defect in all oxidative phosphorylation complexes containing mtDNA-encoded subunits, due to a severe decrease in all mitochondrial mRNAs.
Although this interaction does not depend on mitochondrial mRNA, both proteins show reduced stability in its absence. These results implicate LRPPRC in posttranscriptional mitochondrial gene expression as part of a ribonucleoprotein complex that regulates the stability and handling of mature mRNAs. Tissue-specific disruption of LRPPRC in heart causes mitochondrial cardiomyopathy with drastic reduction in steady-state levels of most mitochondrial mRNAs. LRPPRC forms an RNA-dependent protein complex that is necessary for maintaining a pool of non-translated mRNAs in mammalian mitochondria. Loss of LRPPRC does not only decrease mRNA stability, but also leads to loss of mRNA polyadenylation and the appearance of aberrant mitochondrial translation.
Studies on the in vivo role of SLIRP in regulation of mitochondrial DNA (mtDNA) gene expression revealed that it stabilizes its interacting partner protein LRPPRC by protecting it from degradation. Although SLIRP is completely dependent on LRPPRC for its stability, reduced levels of LRPPRC persist in the absence of SLIRP in vivo. In contrast to LRPPRC, SLIRP is dispensable for polyadenylation of mtDNA-encoded mRNAs, but is required for proper association of mRNAs to the mitochondrial ribosome and efficient translation. In lung cancer cells, SLIRP ha salso been found to interact with Bcl-2, the main antiapoptotic protein. Although SLIRP is not involved in mediating Bcl-2 ability to protect from apoptosis and oxidative damage, Bcl-2 binds and stabilizes SLIRP protein and regulates mitochondrial mRNA levels.
SLIRP and autoimmunity: the wrong regulation “goes viral”
Autoimmune diseases are characterized by the aberrant activation of the immune response, in which the body’s immune system attacks its own tissues, leading to chronic inflammation and tissue damage. Among multiple possible etiologies in autoimmunity, one emerging trigger for the dysregulated immune activation is the immune system’s inability to distinguish self and non-self signatures. One representative non-self signature that can activate the immune response is long double-stranded RNAs (dsRNAs), which are generally produced during viral replication.
Due to their immunogenic nature, the expression and recognition of dsRNAs are strictly regulated. The dsRNAs encoded by the nuclear genome are mostly suppressed through epigenetic modification, but there is another cellular dsRNA to keep under watch: those derived from mitochondial DNA. mt-dsRNAs are generated due to bidirectional transcription of the mitochondrial circular genome. Recently, studies reported the misregulation of mt-dsRNAs in diseases that accompany aberrant immune activation, such as osteoarthritis, Sjogren disesase and alcohol-associated liver disease.
Scientists at KAIST now found an amplification of antiviral signaling by SLIRP through the stabilization of mtRNAs, leading to a robust IFN response to exogenous dsRNAs. According to this investigation, activation of MDA5 by dsRNAs and downstream IFN response upregulates SLIRP and facilitates SLIRP localization to mitochondria through an enhanced mitochondrial import system, especially TOMM40. This study also demonstrated the dual function of SLIRP in different contexts. In cells infected with human beta coronavirus OC43 and encephalo-myocarditis virus (EMCV), SLIRP suppression led to reduced antiviral responses and increased viral replication.
Meanwhile, in the blood and salivary gland cells of Sjögren’s syndrome patients, where both SLIRP and mt-dsRNA levels were elevated, suppressing SLIRP alleviated the abnormal immune response. Although data were variable, scientists found the upregulation of SLIRP in the monocytes of Sjogren disease and systemic lupus together with the upregulation of mtRNAs. In addition, the downregulation of SLIRP in the primary minor salivary gland cells from patients with Sogren resulted in a moderate reduction in the expression of selected ISGs, though one patient with low baseline ISG levels showed no further decrease upon SLIRP knockdown.
One possibility is that targeting SLIRP might provide benefits to patients with high interferon-stimulated gene signatures. These findings highlight SLIRP as a key molecular switch that regulates immune responses in both infections and autoimmune diseases.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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