Aging-induced IL27Ra signaling impairs hematopoietic stem cells.

Hematopoietic stem cell (HSC) aging correlates with an increasing risk of myeloproliferative disease and immunosenescence. In this study, we show that aging-related inflammation promotes HSC aging through tumor necrosis factor-α (TNF-α)→ERK→ETS1→interleukin27Ra (IL27Ra) pathway. TNF-α, a well-known biomarker of inflammation, increases during aging and induces the expression of IL27Ra on HSCs via ERK-ETS1 signaling. Deletion of IL27Ra rescues the functional decline and myeloid bias of HSCs and also reverses the inhibitory effect of TNF-α on HSCs. Aged IL27Ra-/- mice had a reduced proportion of myeloid-biased HSCs and did not display the biased myeloid differentiation that occurs in aged wild-type mice. IL27Ra+ HSCs exhibit impaired reconstitution capacity and myeloid-bias compared with IL27Ra- HSCs and serve as a myeloid-recovery pool upon inflammatory insult. Inflammation-related genes were enriched in IL27Ra+ HSCs and this enrichment increases with aging. Our study demonstrates that age-induced IL27Ra signaling impairs HSCs and raises the possibility that interfering with IL27Ra signaling can counter the physiologically deleterious effect of aging on hematopoietic capacity.

NK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation.

Activation of metabolic signalling by IL-15 is required for natural killer (NK) cell development. Here we show that Tsc1, a repressor of mTOR, is dispensable for the terminal maturation, survival and function of NK cells but is critical to restrict exhaustive proliferation of immature NK cells and activation downstream of IL-15 during NK cell development. Tsc1 is expressed in immature NK cells and is upregulated by IL-15. Haematopoietic-specific deletion of Tsc1 causes a marked decrease in the number of NK cells and compromises rejection of 'missing-self' haematopoietic tumours and allogeneic bone marrow. The residual Tsc1-null NK cells display activated, pro-apoptotic phenotype and elevated mTORC1 activity. Deletion of Raptor, a component of mTORC1, largely reverses these defects. Tsc1-deficient NK cells express increased levels of T-bet and downregulate Eomes and CD122, a subunit of IL-15 receptor. These results reveal a role for Tsc1-dependent inhibition of mTORC1 activation during immature NK cell development.

The Arabidopsis SUMO E3 Ligase AtMMS21 Dissociates the E2Fa/DPa Complex in Cell Cycle Regulation.

Development requires the proper execution and regulation of the cell cycle via precise, conserved mechanisms. Critically, the E2F/DP complex controls the expression of essential genes during cell cycle transitions. Here, we discovered the molecular function of the Arabidopsis thaliana SUMO E3 ligase METHYL METHANESULFONATE SENSITIVITY GENE21 (AtMMS21) in regulating the cell cycle via the E2Fa/DPa pathway. DPa was identified as an AtMMS21-interacting protein and AtMMS21 competes with E2Fa for interaction with DPa. Moreover, DPa is a substrate for SUMOylation mediated by AtMMS21, and this SUMOylation enhances the dissociation of the E2Fa/DPa complex. AtMMS21 also affects the subcellular localization of E2Fa/DPa. The E2Fa/DPa target genes are upregulated in the root of mms21-1 and mms21-1 mutants showed increased endoreplication. Overexpression of DPa affected the root development of mms21-1, and overexpression of AtMMS21 completely recovered the abnormal phenotypes of 35S:E2Fa-DPa plants. Our results suggest that AtMMS21 dissociates the E2Fa/DPa complex via competition and SUMOylation in the regulation of plant cell cycle.

SUMO E3 ligase AtMMS21 is required for normal meiosis and gametophyte development in Arabidopsis.

BACKGROUND: MMS21 is a SUMO E3 ligase that is conserved in eukaryotes, and has previously been shown to be required for DNA repair and maintenance of chromosome integrity. Loss of the Arabidopsis MMS21 causes defective meristems and dwarf phenotypes. RESULTS: Here, we show a role for AtMMS21 during gametophyte development. AtMMS21 deficient plants are semisterile with shorter mature siliques and abortive seeds. The mms21-1 mutant shows reduced pollen number, and viability, and germination and abnormal pollen tube growth. Embryo sac development is also compromised in the mutant. During meiosis, chromosome mis-segregation and fragmentation is observed, and the products of meiosis are frequently dyads or irregular tetrads. Several transcripts for meiotic genes related to chromosome maintenance and behavior are altered. Moreover, accumulation of SUMO-protein conjugates in the mms21-1 pollen grains is distinct from that in wild-type. CONCLUSIONS: Thus, these results suggest that AtMMS21 mediated SUMOylation may stabilize the expression and accumulation of meiotic proteins and affect gametophyte development.

AtMMS21 regulates DNA damage response and homologous recombination repair in Arabidopsis.

DNA damage is a significant problem in living organisms and DNA repair pathways have been evolved in different species to maintain genomic stability. Here we demonstrated the molecular function of AtMMS21, a component of SMC5/6 complex, in plant DNA damage response. Compared with wild type, the AtMMS21 mutant plants show hypersensitivity in the DNA damaging treatments by MMS, cisplatin and gamma radiation. However, mms21-1 is not sensitive to replication blocking agents hydroxyurea and aphidicolin. The expression of a DNA damage response gene PARP2 is upregulated in mms21-1 under normal condition, suggesting that this signaling pathway is constitutively activated in the mutant. Depletion of ATAXIA-TELANGIECTASIA MUTATED (ATM) in mms21-1 enhances its root growth defect phenotype, indicating that ATM and AtMMS21 may play additive roles in DNA damage pathway. The analysis of homologous recombination frequency showed that the number of recombination events is reduced in mms21-1 mutant. Conclusively, we provided evidence that AtMMS21 plays an important role in homologous recombination for DNA damage repair.

Emerging role of SUMOylation in plant development.

Post-translational attachment of small ubiquitin-like modifier (SUMO), defined as SUMOylation, has emerged as a new mechanism of protein regulation in plant biology. In plant, SUMOylation has been shown to play crucial roles in a variety of biotic and abiotic stress responses. Recent work using viable mutants with defective SUMOylation have indicated an important role for SUMOylation in a wide range of developmental processes, such as cell division, expansion, survival and differentiation, vegetative growth and reproductive development. This review will summarize the currently emerging information regarding the function of SUMOylation in plant development.

AtMMS21, an SMC5/6 complex subunit, is involved in stem cell niche maintenance and DNA damage responses in Arabidopsis roots.

Plants maintain stem cells in meristems to sustain lifelong growth; these stem cells must have effective DNA damage responses to prevent mutations that can propagate to large parts of the plant. However, the molecular links between stem cell functions and DNA damage responses remain largely unexplored. Here, we report that the small ubiquitin-related modifier E3 ligase AtMMS21 (for methyl methanesulfonate sensitivity gene21) acts to maintain the root stem cell niche by mediating DNA damage responses in Arabidopsis (Arabidopsis thaliana). Mutation of AtMMS21 causes defects in the root stem cell niche during embryogenesis and postembryonic stages. AtMMS21 is essential for the proper expression of stem cell niche-defining transcription factors. Moreover, mms21-1 mutants are hypersensitive to DNA-damaging agents, have a constitutively increased DNA damage response, and have more DNA double-strand breaks (DSBs) in the roots. Also, mms21-1 mutants exhibit spontaneous cell death within the root stem cell niche, and treatment with DSB-inducing agents increases this cell death, suggesting that AtMMS21 is required to prevent DSB-induced stem cell death. We further show that AtMMS21 functions as a subunit of the STRUCTURAL MAINTENANCE OF CHROMOSOMES5/6 complex, an evolutionarily conserved chromosomal ATPase required for DNA repair. These data reveal that AtMMS21 acts in DSB amelioration and stem cell niche maintenance during Arabidopsis root development.