Abstract
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.
Highlights
Innate immunity and apoptosis are intertwined defense responses of multicellular organisms to various environmental cues
NH2-terminal ARM-eGFP was observed in the nucleus, but did not form the thread-like lattice seen with full-length Sterile alpha and armadillo-motif containing protein (SARM), suggesting that the protein-protein interaction domain sterile alpha motifs (SAM), absent in the nuclear-translocated ARM-eGFP fusion protein, may contribute to the nuclear lattice pattern
The use of eGFP to track intracellular trafficking of SARM in human cells is consistent with the common application of eGFP in studies of the subcellular localization and function of several proteins, including those involved in apoptosis [26,27,28,29,30]
Summary
Innate immunity and apoptosis are intertwined defense responses of multicellular organisms to various environmental cues. The mainstays of innate immunity are molecular pattern recognition receptors known as Toll-like receptors (TLRs) that sense invading microbes. The TLR family consists of 10 known human receptors which recognize ubiquitous pathogen-associated molecular patterns. TLRs interact with select members of the MyD88 family of intracellular adaptor proteins. These receptor-adaptor interactions are mediated by a tollinterleukin-1 receptor (TIR) domain. The TIR domain represents a common structural unit in all members of the TLR family as well as all members of the MyD88 family of adaptor proteins [1] Through TIR-TIR receptor-adaptor and/or adaptor-adaptor interactions, intracellular pro-inflammatory signaling cascades are propagated resulting in increased expression of pro-inflammatory and pro-apoptotic genes [1]. Apoptosis can ensue as a result of these signaling cascades [1,2,3]
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