The innate immunity adaptor SARM translocates to the nucleus to stabilize lamins and prevent DNA fragmentation in response to pro-apoptotic signaling.
Sterile alpha and armadillo-motif containing protein (SARM), a highly conserved and structurally unique member of the MyD88 family of Toll-like receptor adaptors, plays an important role in innate immunity signaling and apoptosis. Its exact mechanism of intracellular action remains unclear. Apoptosis is an ancient and ubiquitous process of programmed cell death that results in disruption of the nuclear lamina and, ultimately, dismantling of the nucleus. In addition to supporting the nuclear membrane, lamins serve important roles in chromatin organization, epigenetic regulation, transcription, nuclear transport, and mitosis. Mutations and other damage that destabilize nuclear lamins (laminopathies) underlie a number of intractable human diseases. Here, we report that SARM translocates to the nucleus of human embryonic kidney cells by using its amino-terminal Armadillo repeat region. Within the nucleus, SARM forms a previously unreported lattice akin to the nuclear lamina scaffold. Moreover, we show that SARM protects lamins from apoptotic degradation and reduces internucleosomal DNA fragmentation in response to signaling induced by the proinflammatory cytokine Tumor Necrosis Factor alpha. These findings indicate an important link between the innate immunity adaptor SARM and stabilization of nuclear lamins during inflammation-driven apoptosis in human cells.
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
Chad R
CR
Sethman
Jacek
J
Hawiger
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism*; D053178:Caspase 6 / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D053938:DNA Fragmentation; D015870:Gene Expression; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D034882:Lamins / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D051186:Armadillo Domain Proteins; D003598:Cytoskeletal Proteins; D034882:Lamins; C435689:SARM1 protein, human; D014409:Tumor Necrosis Factor-alpha; D053178:Caspase 6