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DNases (endonucleases) - Coggle Diagram
DNases (endonucleases)
DNase1 family
divalent cations (Ca2+ or Mg2+), peak activity at neutral pH, leaves 5' phosphates
DNase1l1
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ater cleavage of signal sequence: remains anchored to membrane by GPI anchor -> localized to membrane and ER
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DNase1l2
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might reside in ER, could also be in lysosomes, intracellular function described
Acts intracellularly during keratinocyte differentiation (gains access to nucelus after organelle disruption)
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DNase1
Expressed primarily by exocrine cells of digestive tract (in saliva, intestine, pamcreaskidneys and urine) -> sigestion of dietary DNA, also present in blood (main serum nuclease in mice)
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degrades naked DNA, but also chromatin -> plasmin (peptidase im blutserum) removed proteins from chromatin, enables digestion by DNase1
DNase 1 locus consists of 9 exons -> last one overlaps with Trap1 gene (mitochondiral survival protein belonging to heat shock protein 90 family)
DNase1l3
Present in blood, but mainly secreted by myeloid cells from liver and spleen (DCs and macrophages, also in other tissues), low levels also in B1a, MZ B cells and pDCs
Mainly secreted after cleavage of signal sequence, but intracellular function described
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SLE and DNase1l3
complete KO causes pediatric-onset rather than adult-onset lupus in humans (pediatric onset is characterized by no gender bias, more nephritis and mainly anti-dsDNA Abs and anti-neutrophil cytoplasmic Abs (ANCA))
incomplete KO: associated wih SLE and hypocomplementemic urticarial vasculitis (HUVS -> decerased C1q, serum complement activation, arthritis, urticarial vasculitis, glomerulonephritis, but not dsDNA Abs and ANCA)
KO mice on B6 and mixed B6x129 background develop SLE -> early onset dsDNA Abs (5 weeks), later other Abs, immune activation and pathology -> better model for pediatric-onset SLE?
Intracellular functions: DNase1l3 inhibition blocks IL1b secretion from macrophages -> therefore delayed immune activation?
autoimmunity in DNase1l3 KO mice not dependet on intracellular DNA sensor STING -> extracellular role of DNase1l3
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Signal sequence prior to DNase domain (directs insertion into ER) -> signal sequence can inhibit DNase activity
DNase2 family
does not require cations, peak activity at acidic pH, leaves 3'phosphates
DNase2a
Widely expressed through tissues, high expression in macrophages
Embrionic lethal, rheumatoid arthritis, mild associtation with SLE
DNase2b
Mainly expressed in lens of eye, salivary glands and lungs
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L-DaseII
Widely expressed throughout tissue, Expressed in macrophages and neutrophils
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Achitecture: Main feature is DNase domain (spans majority of protein) -> four-layered a-helix/b-sandwich
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