Dnase1 Family in Autoimmunity: History
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Contributor:
Peter A. Keyel

The deoxyribonuclease 1 (Dnase1) family is a key family of endonucleases that degrades DNA. Loss of Dnase1 family function causes several diseases where the host’s immune system targets the host, such as systemic lupus erythematosus, hypocomplementemic urticarial vasculitis syndrome. 

  • nuclease
  • lupus
  • ehrlichiosis
  • psoriasis
  • HUVS
  • NETs
  • cell-free DNA

Discovery of Dnase1 Family Members

Deoxyribonuclease (Dnase) activity was described in bovine organs in the 1800s, and the proteins responsible for this activity have been characterized over the last century. In the early 1900s, digestion of nucleic acids by liver, spleen, pancreas, and other organs was investigated. As reviewed [1], the enzymatic activity was given a succession of names, including desoxyribonuclease, and determined to function optimally at neutral pH [2]. The founding member of the Dnase1 family, Dnase1, was isolated and crystallized in 1950 [1]. Dnase1 activity was generally recognized to require divalent cations (Ca2+ or Mg2+), to act optimally at neutral pH, and to leave 5′ phosphates following DNA cleavage [1][2][3][4]. As reviewed [5], in 1947 a second, “acid DNase” activity was described in mammals [6]. Acid DNase activity had an ubiquitous tissue distribution and showed peak activity at acidic pH [5]. To distinguish the acid DNase from the pancreatic DNase, which was called Dnase I, and later Dnase1, the term Dnase II (later Dnase2) was suggested as an alternative to acid DNase [3]. Dnase2 has no requirement for divalent cations and hydrolyzes double stranded DNA into short oligonucleotides bearing 3′ -phosphate groups [5]. Multiple proteins possess acid and neutral DNase activity. The Dnase II/Dnase2 family now consists of Dnase2a, Dnase2b, and L-Dnase II/SerpinB1 [7]. In the 1990s, three new members of the Dnase I family were discovered, and termed “DNase1-like” proteins: Dnase1L1, Dnase1L2, and Dnase1L3 [8][9][10][11][12][13]. Dnase1-like 1 (Dnase1L1) was discovered in 1995 and first named human Dnase I lysosomal-like (DNL1L) [8]. Dnase1L2 was first described in 1997, during the gene mapping of the Dnase1 [9]. Finally, Dnase1L3 was identified in 1994 from nuclei of rat thymocytes as the third of three nucleases and consequently termed ‘Dnase γ’ [12]. Dnase1L3 was also called novel human Dnase (nhDnase) [13], and liver/spleen DNase (LS-Dnase) [14].
Dnase1 family members often show restricted tissue expression. In humans, Dnase1 is primarily secreted in saliva, intestine, pancreas, kidneys, and urine, but is also present in serum [1][15]. Dnase1L1 is restricted to skeletal muscle and cardiomyocytes [16]. Dnase1L2 is primarily restricted to keratinocytes, and tissues containing them, like the skin [17]. Dnase1L3 is secreted into blood, primarily by myeloid cells [18]. Distinct Dnase1 family members enable tissue-specific DNA degradation, dependent on the function of that tissue. Overall, Dnases are essential for DNA degradation in most animals.

Evolution of Dnases

Consistent with an essential role for DNA degradation, all Dnase1 family members are widely expressed throughout Metazoa. The phylogenetic distribution of Dnase1 and Dnase1L3 in Animalia predicts that Dnase1L3 is closest to the common ancestral Dnase [19]. Dnase1L3 is present in animals from humans down to corals and sponges, whereas the phylogenetically lowest organism containing both Dnase1 and Dnase1L3 is the placozoan Trichoplax adhaerens [19]. Interestingly, Dnase1 and Dnase1L3 are absent in Protostomia, including arthropods and nematodes [19], though nematodes express Dnase2 [20]. A role for Dnase1 family members in digestion has been proposed for sponges [19]. Both Dnase1 and Dnase1L3 may act in this role in phylogenetically lower organisms, with specialization between these enzymes potentially occurring in higher organisms. For example, the sponge Amphimedon queenslandica secretes Dnase1L3 to digest DNA from its prey [19]. However, some specialization between neutral and acid Dnases is present in sponges. The orange sea sponge Tethya aurantium has both neutral and acid Dnases, which show functional specialization [21]. The Dnase1 activity is present in the cortex, which interacts with the environment, while acid Dnase is expressed in endosomes to facilitate digestion [21]. Overall, the Dnase1 family represents a highly conserved enzyme family for removing DNA.

Extranuclear DNA Is Inflammatory

Removal of DNA is needed not just for digestion, but also to prevent aberrant inflammation. One key danger signal indicating infection or damage in animals is DNA found outside of its expected locations in the nucleus or mitochondria. Consequently, DNA is a potent inducer of inflammation and autoimmunity. Inflammation and cell death can be triggered after cytoplasmic DNA is sensed by several intracellular DNA sensors, including STimulator of INterferon Genes (STING) and Absent In Melanoma 2 (AIM2) [22]. Toll-like Receptor 9 (TLR9) can sense extracellular DNA [22]. Inflammatory DNA is produced during immunity by the release of Neutrophil Extracellular Traps (NETs). NETs are networks of polynucleosomes released from activated neutrophils that primarily consist of chromatin and histones [23]. These 15–17 nm diameter fibers are lined with antimicrobial enzymes and peptides. NETs are used by neutrophils to kill pathogens. NETs are primarily released by NETosis. NETosis is a form of programmed cell death wherein chromatin, nuclear, and granular contents are decondensed and released in the extracellular area [23]. While effective for clearing pathogens, the failure to degrade NETs causes harmful inflammatory responses [24]. DNA in NETs can be internalized and activate STING, leading to the release of pro-inflammatory interferons [25]. DNA is also antigenic. Anti-DNA antibodies characterize several autoimmune diseases, including Systemic Lupus Erythematosus [26]. Anti-DNA-DNA immune complexes promote Complement deposition, inflammation, and tissue damage [26]. Consequently, DNA degradation after necrosis or programmed cell death is critical to preventing autoimmunity. While the intracellular Dnase2a promotes DNA degradation after phagocytosis, Dnase1 family members degrade DNA prior to phagocytosis [7]. Thus, the Dnase1 family plays a key role in preventing autoimmunity from a host’s own DNA, due to its catalytic ability to degrade DNA.

References

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  2. Levene, P.A.; Medigreceanu, F. On Nucleases. J. Biol. Chem 1911, 9, 65–83.
  3. Cunningham, L.; Laskowski, M. Presence of two different desoxyribonucleode-polymerases in veal kidney. Biochim. Biophys. Acta 1953, 11, 590–591.
  4. Shiokawa, D.; Tanuma, S. Characterization of human DNase I family endonucleases and activation of DNase gamma during apoptosis. Biochemistry 2001, 40, 143–152.
  5. MacLea, K.S.; Krieser, R.J.; Eastman, A. A family history of deoxyribonuclease II: Surprises from Trichinella spiralis and Burkholderia pseudomallei. Gene 2003, 305, 1–12.
  6. Catcheside, D.G.; Holmes, B. The action of enzymes on chromosomes. Symp. Soc. Exp. Biol. 1947, 225–231.
  7. Keyel, P.A. Dnases in health and disease. Dev. Biol. 2017, 429, 1–11.
  8. Parrish, J.E.; Ciccodicola, A.; Wehhert, M.; Cox, G.F.; Chen, E.; Nelson, D.L. A muscle-specific DNase I-like gene in human Xq28. Hum. Mol. Genet. 1995, 4, 1557–1564.
  9. Rodriguez, A.M.; Rodin, D.; Nomura, H.; Morton, C.C.; Weremowicz, S.; Schneider, M.C. Identification, localization, and expression of two novel human genes similar to deoxyribonuclease I. Genomics 1997, 42, 507–513.
  10. Shiokawa, D.; Hirai, M.; Tanuma, S. cDNA cloning of human DNase gamma: Chromosomal localization of its gene and enzymatic properties of recombinant protein. Apoptosis 1998, 3, 89–95.
  11. Liu, Q.Y.; Pandey, S.; Singh, R.K.; Lin, W.; Ribecco, M.; Borowy-Borowski, H.; Smith, B.; LeBlanc, J.; Walker, P.R.; Sikorska, M. DNaseY: A rat DNaseI-like gene coding for a constitutively expressed chromatin-bound endonuclease. Biochemistry 1998, 37, 10134–10143.
  12. Shiokawa, D.; Ohyama, H.; Yamada, T.; Takahashi, K.; Tanuma, S. Identification of an endonuclease responsible for apoptosis in rat thymocytes. Eur. J. Biochem. 1994, 226, 23–30.
  13. Zeng, Z.; Parmelee, D.; Hyaw, H.; Coleman, T.A.; Su, K.; Zhang, J.; Gentz, R.; Ruben, S.; Rosen, C.; Li, Y. Cloning and characterization of a novel human DNase. Biochem. Biophys. Res. Commun. 1997, 231, 499–504.
  14. Baron, W.F.; Pan, C.Q.; Spencer, S.A.; Ryan, A.M.; Lazarus, R.A.; Baker, K.P. Cloning and characterization of an actin-resistant DNase I-like endonuclease secreted by macrophages. Gene 1998, 215, 291–301.
  15. Kishi, K.; Yasuda, T.; Takeshita, H. DNase I: Structure, function, and use in medicine and forensic science. Leg. Med. 2001, 3, 69–83.
  16. Los, M.; Neubuser, D.; Coy, J.F.; Mozoluk, M.; Poustka, A.; Schulze-Osthoff, K. Functional characterization of DNase X, a novel endonuclease expressed in muscle cells. Biochemistry 2000, 39, 7365–7373.
  17. Fischer, H.; Eckhart, L.; Mildner, M.; Jaeger, K.; Buchberger, M.; Ghannadan, M.; Tschachler, E. DNase1L2 degrades nuclear DNA during corneocyte formation. J. Investig. Dermatol. 2007, 127, 24–30.
  18. Sisirak, V.; Sally, B.; D’Agati, V.; Martinez-Ortiz, W.; Ozcakar, Z.B.; David, J.; Rashidfarrokhi, A.; Yeste, A.; Panea, C.; Chida, A.S.; et al. Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity. Cell 2016, 166, 88–101.
  19. Ueki, M.; Kimura-Kataoka, K.; Takeshita, H.; Fujihara, J.; Iida, R.; Sano, R.; Nakajima, T.; Kominato, Y.; Kawai, Y.; Yasuda, T. Evaluation of all non-synonymous single nucleotide polymorphisms (SNPs) in the genes encoding human deoxyribonuclease I and I-like 3 as a functional SNP potentially implicated in autoimmunity. FEBS J. 2014, 281, 376–390.
  20. Lyon, C.J.; Evans, C.J.; Bill, B.R.; Otsuka, A.J.; Aguilera, R.J. The C. elegans apoptotic nuclease NUC-1 is related in sequence and activity to mammalian DNase II. Gene 2000, 252, 147–154.
  21. Fafandel, M.; Ravlic, S.; Smodlaka, M.; Bihari, N. Deoxyribonucleases (DNases) in the cortex and endosome from the marine sponge Tethya aurantium. Russ. J. Mar. Biol. 2010, 36, 383–389.
  22. Kumar, V. The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA. Front. Immunol. 2020, 11, 624597.
  23. Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, D.S.; Weinrauch, Y.; Zychlinsky, A. Neutrophil extracellular traps kill bacteria. Science 2004, 303, 1532–1535.
  24. Kaplan, M.J.; Radic, M. Neutrophil extracellular traps: Double-edged swords of innate immunity. J. Immunol. 2012, 189, 2689–2695.
  25. Apel, F.; Andreeva, L.; Knackstedt, L.S.; Streeck, R.; Frese, C.K.; Goosmann, C.; Hopfner, K.P.; Zychlinsky, A. The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps. Sci. Signal. 2021, 14.
  26. Soni, C.; Reizis, B. DNA as a self-antigen: Nature and regulation. Curr. Opin. Immunol. 2018, 55, 31–37.
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