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Loss of Mitochondrial Protease CLPP Activates Type I Interferon Responses Through The bioRxiv preprint doi: https://doi.org/10.1101/2020.08.30.274712; this version posted August 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Loss of mitochondrial protease CLPP activates type I interferon responses through the 2 mtDNA-cGAS-STING signaling axis. 3 4 Sylvia Torres-Odio*, Yuanjiu Lei*, Suzana Gispert†, Antonia Maletzko†, Jana Key†, Saeed 5 Menissy*, Ilka Wittig‡, Georg Auburger†, A. Phillip West*# 6 7 *Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M 8 University Health Science Center, Bryan, TX 77807, USA 9 †Experimental Neurology and ‡Functional Proteomics, Faculty of Medicine, Goethe University, 10 60590 Frankfurt am Main, Germany 11 12 # Correspondence to: [email protected] 13 14 Abstract 15 Caseinolytic mitochondrial matrix peptidase proteolytic subunit, CLPP, is a serine protease that 16 degrades damaged or misfolded mitochondrial proteins. CLPP null mice exhibit growth 17 retardation, deafness, and sterility, resembling human Perrault syndrome (PS), but also display 18 immune system alterations. However, the molecular mechanisms and signaling pathways 19 underlying immunological changes in CLPP null mice remain unclear. Here we report the steady 20 state activation of type I interferon (IFN-I) signaling and antiviral gene expression in CLPP 21 deficient cells and tissues. Depletion of the cyclic GMP-AMP (cGAS)-Stimulator of Interferon 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.30.274712; this version posted August 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 22 Genes (STING) DNA sensing pathway ablates heightened IFN-I responses and abrogates the 23 broad viral resistance phenotype of CLPP null cells. Moreover, we report that CLPP deficiency 24 leads to mitochondrial DNA (mtDNA) instability and packaging alterations. Pharmacological and 25 genetic approaches to deplete mtDNA or inhibit cytosolic release markedly reduce antiviral gene 26 expression, implicating mtDNA stress as the driver of IFN-I signaling in CLPP null mice. Our 27 work places the cGAS-STING-IFN-I innate immune pathway downstream of CLPP and may have 28 implications for understanding myriad human diseases involving CLPP dysregulation. 29 30 31 Introduction 32 Mitochondrial proteases are key modulators of several mitochondrial functions, including the 33 maturation of proteins, maintenance of protein quality control, control of mitochondrial gene 34 expression and biogenesis, mitophagy, and apoptosis (Quirós et al., 2015). CLPP, caseinolytic 35 mitochondrial matrix peptidase proteolytic subunit, is a highly conserved, processive serine 36 protease located in the mitochondrial matrix. CLPP is the protease component of the CLPXP 37 complex that cleaves peptides and various proteins in an ATP-dependent process, together with 38 chaperone and ATPase CLPX (Baker and Sauer, 2012). While prokaryotic ClpXP has been 39 extensively studied, the role and function of CLPXP in mitochondria remain less clear, and there 40 is limited information regarding its specific substrates (Bhandari et al., 2018). Studies in C. elegans 41 have implicated CLPXP as a key component of the mitochondrial unfolded protein response 42 (UPRmt), and downstream signaling and transcriptional responses of the UPRmt are attenuated in 43 worms lacking CLPP activity (Haynes et al., 2007; Pellegrino et al., 2014). Mammalian CLPP is 44 involved in pleiotropic cellular functions such as myoblast differentiation, cell proliferation, and 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.30.274712; this version posted August 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 45 mitoribosome assembly, which controls the rate of mitochondrial protein synthesis (Deepa et al., 46 2016; Szczepanowska et al., 2016). Moreover, CLPP has recently been implicated in cancer, and 47 hyperactivating CLPP was shown to alter mitochondrial function and selectively kill some cancer 48 cells (Ishizawa et al., 2019). Thus, CLPP is being studied as a biological target of anti-cancer drugs 49 in current clinical trials (Graves et al., 2019). 50 Studies performed in CLPP null mice (CLPP-KO) highlight the physiological and 51 pathological relevance of this model to the human disorder known as Perrault syndrome (PS). 52 CLPP-KO mice display profound phenotypic changes characterized by growth retardation, 53 deafness, and premature sterility, despite exhibiting only mild mitochondrial bioenergetic deficits 54 (Gispert et al., 2013). Similar phenotypes are also observed in PS, where the genetic component 55 involves autosomal recessive mutations in CLPP and other nuclear DNA-encoded mitochondrial 56 proteins (Jenkinson et al., 2013). Other phenotypes of this mouse include insulin resistance and 57 protection from diet-induced obesity (Bhaskaran et al., 2018), accelerated depletion of ovarian 58 follicular reserve (T. Wang et al., 2018), and impairment of adaptive thermogenesis due to a 59 decline in brown adipocytes (Becker et al., 2018). 60 Interestingly, CLPP-KO mice show activation of antiviral genes, with elevated expression 61 of interferon stimulated genes (ISGs) noted in many tissues and fibroblasts (Gispert et al., 2013; 62 Key et al., 2020). Activation of innate immune signaling downstream of mitochondrial dysfunction 63 has been reported in several mitochondrial mutant animals (Pellegrino et al., 2014; West et al., 64 2015), as well as in animal models of human disease and patient samples (Nakahira et al., 2015; 65 West, 2017; West and Shadel, 2017). Emerging evidence localizes cGAS, Toll-like receptor 9 66 (TLR9), and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome 67 downstream of mitochondrial damage (Nakahira et al., 2015; West, 2017; West and Shadel, 2017). 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.30.274712; this version posted August 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 68 Eukaryotic mitochondria maintain prokaryotic features, including a double-stranded circular DNA 69 genome, inner membrane cardiolipin, and N-formylated proteins, which act as potent triggers of 70 cGAS, TLR9, NLRP3, and other innate immune sensors when released from mitochondria into 71 the cytosol or extracellular space. The release and accumulation of these so-called mitochondrial 72 called damage-associated molecular patterns (DAMPs) is increasingly implicated in the 73 inflammatory pathology of numerous human disorders including autoimmunity, 74 neurodegenerative diseases, and cancer (Nakahira et al., 2015; West and Shadel, 2017; Youle, 75 2019). The mitochondrial molecular mechanisms and innate immune signaling pathways 76 underlying activation of antiviral signatures in CLPP-KO mice remain uncharacterized, and the 77 biological significance of this phenotype is unclear. Moreover, the role of IFN-I signaling in 78 CLPP-KO mouse pathology and its possible implication in human PS remain to be examined. 79 Herein we show that enhanced ISG expression and IFN-I responses in CLPP-KO mice are 80 triggered by mtDNA stress and mediated by the cGAS-STING DNA sensing pathway. Deletion 81 of STING or the interferon a/b receptor (IFNAR) in CLPP-KO MEFs ablates steady state 82 expression of broadly antiviral ISGs and reduces the potent antiviral phenotypes observed during 83 RNA and DNA virus infection. These findings shed light on a new mitochondrial pathway 84 upstream of cGAS and STING, link mitochondrial proteostasis to mtDNA genome maintenance, 85 and may have important implications for understanding mitochondrial-innate immune crosstalk in 86 the context of human health and disease. 87 88 Results and Discussion 89 CLPP deficiency leads to steady state ISG expression and an antiviral signature in cells and 90 tissues 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.30.274712; this version posted August 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 91 We first expanded upon our prior findings that revealed increased steady state expression of 92 antiviral genes in CLPP deficient tissues (Gispert et al., 2013). Using Ingenuity Pathway Analysis 93 (IPA) software, we observed that predicted upstream regulators of the antiviral gene signature in 94 CLPP-KO tissues included factors governing IFN-I signaling (Irf7, Irf3 and Stat1), IFNa, and 95 IFNAR (Fig EV1A). Among the list of upregulated IRF7 and STAT1 target genes, we identified 96 canonical ISGs such as Usp18, Ifit1b, Ifi44, and Rtp4 (Fig EV1B). Individual analyses of heart and 97 liver tissues from 3-5-month-old mice revealed a significant enhancement of ISGs at the protein 98 level in both the liver and heart of CLPP-KO mice (Fig EV1C and D). 99 To better characterize this ISG response, we used mouse embryonic fibroblasts (MEFs) 100 and human foreskin fibroblasts deficient in CLPP. Expression profiles of CLPP-KO MEFs 101 revealed an enrichment of ISGs and antiviral signaling factors at both the RNA and protein level 102 (Fig 1A and B). Among the set of overexpressed
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