SNEVhPrp19/hPso4 Regulates Adipogenesis of Human Adipose Stromal Cells

摘要

class="head no_bottom_margin" id="sec1title">IntroductionAdipose tissue is formed at specific locations as a major energy storage compartment and is an important source of signaling activity. The distribution of adipose reservoirs within the body undergoes major changes during normal aging (), while excess or dysfunctional fat tissue leads to reduced lifespan and accelerates the onset of age-related diseases (, ). Moreover, loss of subcutaneous fat and increased visceral adiposity is observed in patients with segmental progeroid syndromes such as Werner syndrome (), Cockayne syndrome, or trichothiodystrophy. These diseases, mirroring certain aspects of accelerated aging, are characterized by mutations in DNA damage repair (DDR) factors, leading to accumulation of DNA damage over time and hence potentially to reduced proliferation and differentiation or to senescence of pre-adipocytes (). Mouse models deficient in DNA repair also show adipose tissue degeneration (). However, it remains unclear whether DNA repair factors themselves have an impact on adipogenic differentiation of human adipose stromal cells (hASCs).WRN and SNEV^hPrp19/hPso4 are members of a DDR protein complex () and are involved in adipogenesis of mouse 3T3-L1 cells (, ). WRN is a helicase required for DNA recombination and repair and interacts with the SNEV complex during repair of interstrand crosslinks (). However, due to differences in the murine and human adipogenic differentiation processes (), the impact of the human homologs on adipogenesis is still unclear.SNEV^hPrp19/hPso4, termed SNEV in the following, is highly conserved from yeast to humans and plays a role in several cellular pathways. It is an essential splicing factor (), possesses E3 ubiquitin ligase activity (), and interacts with the proteasome (). In addition, SNEV is involved in various types of DDR, such as DNA double-strand break repair () and homologous recombination (href="#bib1" rid="bib1" class=" bibr popnode">Abbas et al., 2014). It also interacts with two major DDR regulators: ataxia-telangiectasia mutated regulator phosphorylates SNEV after exposure to oxidative stress (href="#bib11" rid="bib11" class=" bibr popnode">Dellago et al., 2012), and SNEV contributes to the activation Rad3-related (ATR) regulator (href="#bib38" rid="bib38" class=" bibr popnode">Wan and Huang, 2014). SNEV is also linked to cellular senescence (href="#bib37" rid="bib37" class=" bibr popnode">Voglauer et al., 2006) and skin aging (href="#bib26" rid="bib26" class=" bibr popnode">Monteforte et al., 2016).Here we show that SNEV indeed regulates adipogenesis in human cells and that these findings can be extended to other factors that counteract DNA damage during adipogenic differentiation of hASCs. This suggests that the ability to repair DNA might represent a checkpoint for adipogenesis and thereby provides a failsafe mechanism to reduce the risk of accumulating damaged and/or senescent cells with a pro-inflammatory phenotype in the adipose tissue.