DNA polymerase-alpha regulates the activation of type I interferons through cytosolic RNA:DNA synthesis
Por:
Starokadomskyy, P, Gemelli, T, Rios, JJ, Xing, C, Wang, RC, Li, HY, Pokatayev, V, Dozmorov, I, Khan, S, Miyata, N, Fraile, G, Raj, P, Xu, Z, Xu, ZG, Ma, L, Lin, ZM, Wang, HJ, Yang, Y, Ben-Amitai, D, Orenstein, N, Mussaffi, H, Baselga, E, Tadini, G, Grunebaum, E, Sarajlija, A, Krzewski, K, Wakeland, EK, Yan, N, de la Morena, MT, Zinn, AR, Burstein, E
Publicada:
1 may 2016
Resumen:
Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-alpha. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA: DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA: DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.
Filiaciones:
Starokadomskyy, P:
Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
Gemelli, T:
Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA
Rios, JJ:
Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA
Texas Scottish Rite Hosp Children, Sarah M & Charles E Seay Ctr Musculoskeletal Res, Dallas, TX 75219 USA
Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA
Xing, C:
Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA
Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA
Wang, RC:
Univ Texas SW Med Ctr Dallas, Dept Dermatol, Dallas, TX 75390 USA
Li, HY:
Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
Pokatayev, V:
Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
Dozmorov, I:
Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA
Khan, S:
Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA
Miyata, N:
Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
Fraile, G:
Ramon y Cajal Univ Hosp, Dept Internal Med, Madrid, Spain
Raj, P:
Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA
Xu, Z:
Capital Med Univ, Beijing Childrens Hosp, Dept Dermatol, Beijing, Peoples R China
Xu, ZG:
Capital Med Univ, Beijing Childrens Hosp, Dept Dermatol, Beijing, Peoples R China
Ma, L:
Capital Med Univ, Beijing Childrens Hosp, Dept Dermatol, Beijing, Peoples R China
Lin, ZM:
Peking Univ, Hosp 1, Dept Dermatol, Beijing 100871, Peoples R China
Wang, HJ:
Peking Univ, Hosp 1, Dept Dermatol, Beijing 100871, Peoples R China
Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China
Peking Univ, Acad Adv Interdisciplinary Studies, Beijing 100871, Peoples R China
Yang, Y:
Peking Univ, Hosp 1, Dept Dermatol, Beijing 100871, Peoples R China
Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China
Ben-Amitai, D:
Schneider Childrens Med Ctr Israel, Unit Pediat Dermatol, Petah Tiqwa, Israel
Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel
Orenstein, N:
Schneider Childrens Med Ctr Israel, Genet Unit, Petah Tiqwa, Israel
Mussaffi, H:
Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel
Schneider Childrens Med Ctr, Pulmonol Inst, Petah Tiqwa, Israel
Baselga, E:
Hosp Santa Creu & Sant Pau, Dept Dermatol, Barcelona, Spain
Tadini, G:
Univ Milan, Dept Pathophysiol & Transplantat, Pediat Dermatol Unit, Milan, Italy
Univ Milan, Dept Pathophysiol & Transplantat, Pediat Highly Intens Care Unit, Milan, Italy
IRCCS Ca Granda Osped Maggiore Policlin, Milan, Italy
Grunebaum, E:
Hosp Sick Children, Dev & Stem Cell Biol Program, 555 Univ Ave, Toronto, ON M5G 1X8, Canada
Univ Toronto, Hosp Sick Children, Div Immunol & Allergy, Toronto, ON M5G 1X8, Canada
Sarajlija, A:
Mother & Child Hlth Care Inst Serbia, Belgrade, Serbia
Univ Belgrade, Sch Med, Belgrade, Serbia
Krzewski, K:
NIAID, Immunogenet Lab, Receptor Cell Biol Sect, NIH, Rockville, MD USA
Wakeland, EK:
Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA
Yan, N:
Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA
de la Morena, MT:
Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA
Childrens Hlth, Dallas, TX USA
Zinn, AR:
Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA
Burstein, E:
Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA
Green Accepted
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