Current Biology Vol 19 No 6 R262 auditory stimuli were bound into 5. Tallal, P., Miller, S., and Fitch, R.H. (1993). (2006). Perception of matching and conflicting Neurobiological basis of speech: a case for the audiovisual speech in dyslexic and fluent a unitary construct. preeminence of temporal processing. Ann. NY readers: an fMRI study at 3T. Neuroimage 29, Taken together, these recent studies Acad. Sci. 682, 27–47. 797–807. are providing important insights into 6. Temple, E., Poldrack, R.A., Protopapas, A., 15. Eden, G.F., Jones, K.M., Cappell, K., Gareau, L., Nagarajan, S., Salz, T., Tallal, P., Wood, F.B., Zeffiro, T.A., Dietz, N.A., the neurobiological bases of specific Merzenich, M.M., and Gabrieli, J.D. (2000). Agnew, J.A., and Flowers, D.L. (2004). reading disabilities, and are converging Disruption of the neural response to rapid Neural changes following remediation in acoustic stimuli in dyslexia: evidence from adult developmental dyslexia. Neuron 44, on a multisensory model that better functional MRI. Proc. Natl. Acad. Sci. USA 97, 411–422. links auditory processing deficits with 13907–13912. 16. Shaywitz, B.A., Lyon, G.R., and Shaywitz, S.E. the visual functions that mediate 7. Livingstone, M.S., Rosen, G.D., Drislane, F.W., (2006). The role of functional magnetic and Galaburda, A.M. (1991). Physiological and resonance imaging in understanding reading. This knowledge provides anatomical evidence for a magnocellular defect reading and dyslexia. Dev. Neuropsychol. 30, a better conceptual framework for in developmental dyslexia. Proc. Natl. Acad. 613–632. Sci. USA 88, 7943–7947. 17. Temple, E., Deutsch, G.K., Poldrack, R.A., understanding reading disabilities, 8. Stein, J., and Walsh, V. (1997). To see but not Miller, S.L., Tallal, P., Merzenich, M.M., and and holds great promise for the to read; the magnocellular theory of dyslexia. Gabrieli, J.D. (2003). Neural deficits in children development of more effective Trends Neurosci. 20, 147–152. with dyslexia ameliorated by behavioral 9. Nicolson, R.I., Fawcett, A.J., and Dean, P. remediation: evidence from functional MRI. remediation strategies for the (2001). Developmental dyslexia: the cerebellar Proc. Natl. Acad. Sci. USA 100, 2860–2865. treatment of those suffering from these deficit hypothesis. Trends Neurosci. 24, 18. van Atteveldt, N., Formisano, E., Goebel, R., 508–511. and Blomert, L. (2004). Integration of letters and often debilitating disabilities. 10. Shaywitz, S.E., and Shaywitz, B.A. (2005). speech sounds in the human brain. Neuron 43, Dyslexia (specific reading disability). Biol. 271–282. References Psychiatry 57, 1301–1309. 19. Hairston, W.D., Burdette, J.H., Flowers, D.L., 1. Habib, M. (2000). The neurological basis of 11. Shaywitz, S.E., and Shaywitz, B.A. (2003). Wood, F.B., and Wallace, M.T. (2005). Altered developmental dyslexia: an overview and Dyslexia (specific reading disability). Pediatr. temporal profile of visual-auditory multisensory working hypothesis. Brain 123, 2373–2399. Rev. 24, 147–153. interactions in dyslexia. Exp. Brain Res. 166, 2. Blau, V., van Atteveldt, N., Ekkebus, M., 12. Ramus, F. (2003). Developmental dyslexia: 474–480. Goebel, R., and Blomert, L. (2009). Reduced specific phonological deficit or general neural integration of letters and speech sounds sensorimotor dysfunction? Curr. Opin. links phonological and reading deficits in adult Neurobiol. 13, 212–218. Vanderbilt Brain Institute, Vanderbilt dyslexia. Curr. Biol. 19, 503–508. 13. Ramus, F., Rosen, S., Dakin, S.C., Day, B.L., University, 465 21st Avenue South, 3. Paracchini, S., Scerri, T., and Monaco, A.P. Castellote, J.M., White, S., and Frith, U. (2003). Nashville, TN 37232, USA. (2007). The genetic lexicon of dyslexia. Annu. Theories of developmental dyslexia: insights E-mail: [email protected] Rev. Genomics Hum. Genet. 8, 57–79. from a multiple case study of dyslexic adults. 4. Tallal, P. (1980). Auditory temporal perception, Brain 126, 841–865. phonics, and reading disabilities in children. 14. Pekkola, J., Laasonen, M., Ojanen, V., Autti, T., Brain Lang. 9, 182–198. Jaaskelainen, I.P., Kujala, T., and Sams, M. DOI: 10.1016/j.cub.2009.01.025

Innate Immunity: Cytoplasmic DNA analysis of TLR9-deficient mice revealed the existence of alternative Sensing by the AIM2 Inflammasome DNA-sensing pathways, including those regulating IL-1b maturation and IRF-3-dependent type I IFN Cytoplasmic double-stranded DNA triggers cell death and secretion of the pro- expression [2,5]. Furthermore, while inflammatory cytokine IL-1b in macrophages. Recent reports now describe the TLR9 recognizes foreign DNA in mechanism underlying this observation. Upon sensing of DNA, the HIN-200 endo-lysosomal compartments [6], family member AIM2 triggers the assembly of the inflammasome, culminating DNA delivered to the cytoplasm in -1 activation, IL-1b maturation and pyroptotic cell death. triggers a TLR-independent innate immune response that includes the Kate Schroder1, Daniel A. Muruve2, Many years of intense research secretion of IFNb and IL-1b from and Ju¨rg Tschopp1,* have only begun to explain the macrophages [2,5,7]. By comparison, immunostimulatory effects of DNA. The IFNb is not induced in response to the The innate immune system recognizes first clue came with the discovery of the TLR9 ligand, CpG DNA, in pathogens through an extensive array membrane-bound Toll-like receptor macrophages [8]. of pattern recognition receptors (PRRs) (TLR) family of PRRs. Upon recognition The hunt for the cytoplasmic DNA that detect invariant microbial motifs of PAMPs, TLR pathways trigger sensor(s) then began in earnest. The called pathogen-associated molecular profound changes in regulation, first DNA sensor identified was DAI patterns (PAMPs). DNA is one such including the induction of many (also known as DLM-1/ZBP1), PAMP that is highly immunostimulatory pro-inflammatory cytokines downstream which was shown to trigger a robust when internalized or delivered into the of NFkB, mitogen-activated TBK-1/IRF-3-dependent type I IFN cytoplasm of cells [1,2]. Prokaryotic, (MAP) kinases, and IFN regulatory response. Subsequent reports viral and non-microbial DNA triggers factors (IRFs). Our understanding of suggested, however, that a number of innate immune pathways the immunostimulatory properties of DAI-independent mechanisms also that result in the secretion of pro- foreign DNA was advanced operate [9,10]. A recent report from inflammatory cytokines, in particular significantly by the identification of our group implicated the interleukin-1b (IL-1b), the induction of TLR9, which specifically recognizes ‘inflammasome’ pathway in the anti-viral type I interferons (IFNa/b) [2] unmethylated CpG sequences that are sensing of cytoplasmic DNA, leading and cell death in susceptible cells, such present in prokaryotic DNA but to caspase-1 activation and IL-1b as macrophages [3]. suppressed in mammalian DNA [4]. The maturation [5]. Dispatch R263

Anti-viral Inflammatory responses responses IFNβ IL-1β

Cytoplasmic dsDNA

AIM2 oligomerization DAI? upon dsDNA

IFNβ induction HIN HIN AIM2 PYD PYD

ASC clustering, HIN HIN caspase-1 p202 recruitment

HIN HIN AIM2 PYD PYD PYD PYD CARD ASC CARD CARD IL-1β CARD

Pro-IL-1β cleavage

Caspase Caspase Pro-IL-1β Caspase-1 Caspase Caspase Caspase-1 ‘Priming’ activation e.g. recognition of viral DNA in endo- lysosome by TLR9

Cell death via

Current Biology

Figure 1. Model for activation of the AIM2 inflammasome by cytosolic DNA. AIM2 binds to cytoplasmic dsDNA of viral, bacterial or mammalian origin via its HIN domain and oligomerizes upon interaction with dsDNA in a length-dependent manner. In doing so, AIM2 provides binding sites for the adaptor ASC, through homotypic (PYD) interactions. ASC clustering then allows pro-caspase-1 recruitment, via CARD–CARD interactions, and caspase-1 activation. Activated caspase-1 triggers IL-1b processing and secretion in cells primed by inflammatory stimuli to express pro-IL-1b. If prolonged, caspase-1 activation eventually leads to pyroptotic cell death. In addition, cytosolic DNA elicits the induction of the anti-viral cytokine IFNb, through pathways that are currently unclear but may involve DAI. Signaling by autocrine/paracrine IFNb can regulate the AIM2 inflammasome, as it induces expression of both AIM2 and the AIM2 inflammasome antagonist p202.

Although TLR signaling induces the the maturation of pro-inflammatory molecules (e.g. bacterial expression of IL-1b and IL-18, these cytokines, such as IL-1b. Caspase-1 peptidoglycan, ATP, monosodium are synthesized as inactive activation can also trigger pyroptosis, urate crystals); the exact molecular precursor proteins that require a a form of pro-inflammatory cell death interactions associated with these second signal for caspase-1-mediated distinct from the immunologically silent events are currently unclear but it processing and secretion of the active apoptosis mediated by apoptotic seems likely that this occurs through an cytokine in most cell types [11]. Some such as caspase-3. The indirect mechanism. Upon recognition members of the nucleotide-binding importance of inflammasomes in of these cellular ‘danger’ signals, domain leucine-rich repeat (NLR) regulating inflammatory processes is NALP3 is thought to oligomerize and family of proteins, of which the best highlighted by strong links between recruit the adaptor proteins Cardinal characterized is NALP3, form mutations in single NLRs and human and ASC, the latter via homotypic pyrin intracellular caspase-1-activating inflammatory diseases (reviewed domain interactions. The clustered platforms (‘inflammasomes’) that in [12]). caspase recruitment domains (CARDs) function in concert with other pathways, NALP3 senses both pathogen- of ASC and Cardinal in turn permit the such as TLR signaling, to regulate associated and host-derived binding and activation of the Current Biology Vol 19 No 6 R264 inflammatory caspase-1, resulting in processing of caspase-1 and, in the viability as opposed to signaling or the molecular complex referred to as case of pro-IL-1b-expressing crosstalk between type I IFN and the NALP3 inflammasome. Activated cells, processing and release of inflammasome pathways. caspase-1 cleaves IL-1b and IL-18 into IL-1b [14,15]. Both caspase-1 The physiological situations in which their bioactive forms and triggers their activation and IL-1b processing/ the AIM2 inflammasome pathway secretion. Our recent study indicated release were dependent on AIM2 and might be engaged and its relative that, in addition to the known ASC, but not NALP3 or other human place among the other pathogen- or inflammasome stimulators, the NALP3 HIN-200 family members [13–16]. danger-recognition systems remain inflammasome was activated by Although other HIN-200 family unclear. The AIM2 inflammasome is adenovirus in a DNA-dependent members did not appear to be able suggested to be an additional line of manner [5]. Subsequent investigation to trigger inflammasome formation, defense against dsDNA viruses that revealed that an uncharacterized Roberts et al. [16] reported that the have escaped into the after inflammasome, dependent on ASC mouse HIN-200 protein p202 negatively circumventing other pathways of but not NALP3, was activated by regulates the AIM2 inflammasome, innate immunity, such as the detection transfected cytosolic DNA [5]. because RNA interference-mediated of viral dsDNA by TLR9 during Four new reports [13–16] now posit knockdown of p202 enhanced phagocytosis and the recognition of the HIN-200 family member AIM2 as DNA-induced caspase-1 and virus-induced phagosomal/lysosomal the elusive sensor of cytoplasmic caspase-3 activation [16]. This group stress by the NALP3 inflammasome double-stranded DNA (dsDNA), demonstrated that p202 binds [14]. In combination with the DNA providing new insight into innate viral specifically to dsDNA in a sequence- sensors that lead to IRF-3 activation, defense systems. The results suggest independent but length-dependent this provides a substantial layer of that AIM2 binds directly to cytoplasmic manner, similar to AIM2. p202 contains defense against pathogens that do not DNA and triggers the assembly of an two HIN domains but no pyrin domain; enter the cell via endosomes or AIM2 inflammasome resulting in it is the only HIN-200 family member phagosomes, or manage to escape caspase-1 activation and, in cells to lack a pyrin domain and, therefore, these pathways. It has also been expressing pro-IL-1b, the maturation of to have no potential to interact with suggested that retrotransposons or IL-1b (Figure 1). The requirements of ASC. The authors suggest that p202 self DNA may be recognized by cytoplasmic DNA for IFNb induction antagonizes the AIM2 inflammasome cytoplasmic DNA sensors [16]. The and DNA-dependent cell death are by sequestering dsDNA and by circumstances in which this may occur quite permissive: the only necessity interfering with AIM2–ASC interactions, and their biological significance will is that DNA must be double-stranded and thus the ability to form an require further study. and it was found that immunogenicity inflammasome. The relevance of this In all, these recent reports detailing increases with DNA length [16]. mechanism to humans is currently the sensing of cytoplasmic dsDNA by The source and sequence of unclear, as p202 has no known AIM2 have uncovered some novel cytoplasmic dsDNA appear to ortholog in humans, and a human aspects of inflammasome biology. be unimportant for inflammasome HIN-200 protein lacking a pyrin domain They provide the first demonstration of activation, as viral, bacterial, has yet to be described. inflammasome assembly by a protein mammalian and synthetic dsDNA In addition to activating the outside of the NLR family and could all activate caspase-1 [14,15]. inflammatory and pyroptotic caspase, document the first example of a direct In vitro assays suggested that AIM2 caspase-1, cytoplasmic dsDNA also interaction between an inflammasome interacts directly with dsDNA through triggered the activation of the apoptotic sensor and its ligand. In addition, these its carboxy-terminal HIN domain executioner, caspase-3, in an reports shed some light on the possible [14,15], and preferentially binds dsDNA AIM2-dependent fashion [16]. mechanism that drives the rather than single-stranded DNA [13]. DNA-dependent cell death was inflammatory response against self Incubation with dsDNA induced AIM2 dependent on AIM2, ASC and DNA in patients with the autoimmune oligomerization [14]. Cytoplasmic caspase-1 [14,15]. In keeping with this, disease systemic dsDNA sensing did not seem to be a Fernandes-Alnemri et al. [14] suggest erythematosus (SLE). Both AIM2 and general feature of the human HIN-200 that DNA-dependent cell death p202 fall within susceptibility loci for family, as the other family members, displays the hallmarks of pyroptosis. SLE in humans and mice, and p202 is IFIX, IFI16 and MNDA, appeared to be The question of whether other differentially expressed between constitutively nuclear [14,15]. Of the caspases, such as caspase-3, can lupus-susceptible and lupus-resistant HIN-200 family, only AIM2 co-localized contribute to DNA-dependent cell mice [16]. Further research is required in cytoplasmic ASC speckles when death is currently unresolved. to clarify the involvement of the overexpressed cytoplasmically in 293T Interestingly, although the AIM2 HIN-200 family in this disease. cells (nuclear localization sequences inflammasome was critical for were deleted for proteins with native caspase-1 activation and cell death, References nuclear expression) [15], and only it appeared to be completely 1. Stacey, K.J., Sweet, M.J., and Hume, D.A. (1996). Macrophages ingest and are activated the AIM2 pyrin domain interacted dispensable for IFNb induction in by bacterial DNA. J. Immunol. 157, 2116–2122. with the pyrin domain of ASC in response to cytoplasmic dsDNA. 2. Stetson, D.B., and Medzhitov, R. (2006). immunoprecipitation studies and Knockout of either ASC or caspase-1 or Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. in vitro pull-down assays [13–15]. knockdown of AIM2 failed to block, and Immunity 24, 93–103. AIM2 inflammasome activation by actually potentiated, IFNb induction 3. Stacey, K.J., Ross, I.L., and Hume, D.A. (1993). Electroporation and DNA-dependent cell death cytosolic dsDNA or the dsDNA [15]. This effect is believed to be in murine macrophages. Immunol. Cell. Biol. virus culminated in the a consequence of increased cell 71, 75–85. Dispatch R265

4. Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., 9. Wang, Z., Choi, M.K., Ban, T., Yanai, H., inflammasome. Nat. Immunol., in press Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Negishi, H., Lu, Y., Tamura, T., Takaoka, A., doi: 10.1038/ni.1702. Wagner, H., Takeda, K., et al. (2000). A Toll-like Nishikura, K., and Taniguchi, T. (2008). 14. Fernandes-Alnemri, T., Yu, J.W., Datta, P., receptor recognizes bacterial DNA. Nature 408, Regulation of innate immune responses by DAI Wu, J., and Alnemri, E.S. (2009). AIM2 activates 740–745. (DLM-1/ZBP1) and other DNA-sensing the inflammasome and cell death in response 5. Muruve, D.A., Petrilli, V., Zaiss, A.K., molecules. Proc. Natl. Acad. Sci. USA 105, to cytoplasmic DNA. Nature, in press White, L.R., Clark, S.A., Ross, P.J., Parks, R.J., 5477–5482. doi: 10.1038/nature07710. and Tschopp, J. (2008). The inflammasome 10. Ishii, K.J., Kawagoe, T., Koyama, S., Matsui, K., 15. Hornung, V., Ablasser, A., Charrel-Dennis, M., recognizes cytosolic microbial and host DNA Kumar, H., Kawai, T., Uematsu, S., Bauernfeind, F., Horvath, G., Caffrey, D.R., and triggers an innate immune response. Takeuchi, O., Takeshita, F., Coban, C., et al. Latz, E., and Fitzgerald, K.A. (2009). AIM2 Nature 452, 103–107. (2008). TANK-binding kinase-1 delineates recognizes cytosolic dsDNA and forms a 6. Honda, K., Ohba, Y., Yanai, H., Negishi, H., innate and adaptive immune responses to DNA caspase-1-activating inflammasome with ASC. Mizutani, T., Takaoka, A., Taya, C., and vaccines. Nature 451, 725–729. Nature, in press. doi: 10.1038/nature07725. Taniguchi, T. (2005). Spatiotemporal regulation 11. Netea, M.G., Nold-Petry, C.A., Nold, M.F., 16. Roberts, T.L., Idris, A., Dunn, J.A., Kelly, G.M., of MyD88-IRF-7 signalling for robust type-I Joosten, L.A., Opitz, B., van der Meer, J.H., Burnton, C.M., Hodgson, S., Hardy, L.L., interferon induction. Nature 434, 1035–1040. van de Veerdonk, F.L., Ferwerda, G., Garceau, V., Sweet, M.J., Ross, I.L., et al. 7. Ishii, K.J., Coban, C., Kato, H., Takahashi, K., Heinhuis, B., Devesa, I., et al. (2008). Differential (2009). HIN-200 proteins regulate caspase Torii, Y., Takeshita, F., Ludwig, H., Sutter, G., requirement for the activation of the activation in response to foreign cytoplasmic Suzuki, K., Hemmi, H., et al. (2006). A Toll-like inflammasome for processing and release of IL- DNA. Science, in press. doi: 10.1126/ receptor-independent antiviral response 1{beta} in monocytes and macrophages. Blood, science.1169841. induced by double-stranded B-form DNA. epub ahead of print. Nat. Immunol. 7, 40–48. 12. Martinon, F., and Tschopp, J. (2004). 1 8. Schroder, K., Spille, M., Pilz, A., Lattin, J., Inflammatory caspases: linking an intracellular Department of Biochemistry, University of Bode, K.A., Irvine, K.M., Burrows, A.D., innate immune system to autoinflammatory Lausanne, Epalinges, Switzerland. Ravasi, T., Weighardt, H., Stacey, K.J., et al. diseases. Cell 117, 561–574. 2Department of Medicine, University of (2007). Differential effects of CpG DNA on 13. Burckstummer, T., Baumann, C., Bluml, S., Calgary, Calgary, Alberta, Canada. IFN-beta induction and STAT1 activation in Dixit, E., Durnberger, G., Jahn, H., *E-mail: [email protected] murine macrophages versus dendritic cells: Planyavsky, M., Bilban, M., Colinge, J., alternatively activated STAT1 negatively Bennett, K.L., et al. (2009). An orthogonal regulates TLR signaling in macrophages. proteomic-genomic screen identifies AIM2 J. Immunol. 179, 3495–3503. as a cytoplasmic DNA sensor for the DOI: 10.1016/j.cub.2009.02.011

Plant Development: PIF4 Integrates strongly influenced by environmental conditions. Light has been shown to Diverse Environmental Signals regulate these processes through the modulation of PIF stability, but it is becoming clear that, in addition to light, Flexible adaptation to environmental changes is essential for plants. Recent PIFs are also regulated by other factors. studies suggest that a group of basic helix–loop–helix transcription factors play On the transcriptional level, PIF4 and a central role in the crosstalk between environmental cues and hormone PIF5 are regulated by the circadian signalling. clock. The coinciding regulation of PIFs at the transcript and protein Doris Lucyshyn and Philip A. Wigge* be crucial for mediating certain effects level by the clock and light quality, of light on plant development. Plants respectively, ensures that plant growth Since plants are sessile, they must use light not just as an energy source takes place in the early hours before be able to sense changes and adapt but, in combination with ambient sunrise, providing optimal conditions their development to the environment. temperature, day length and light for growth [4,5]. However, as alluded Development continues throughout quality, also to provide seasonal to above, the R:FR ratio is not the the life-cycle of the plant, providing cues. An important measure of light only important factor regulating PIF a rich system to study how biological quality is the ratio of red to far-red function. It was established last year systems perceive multiple light (R:FR), since increased amounts that PIFs are also regulated by the environmental cues and integrate this of FR indicate shading. In Arabidopsis, gibberellin-signalling pathway via information to control development. an exquisitely sensitive and complex DELLA proteins. DELLAs, which are Light and temperature are two pathway relays signals from sensor growth-repressing transcriptional particularly important environmental proteins called phytochromes to regulators, were shown to interact cues for plant growth and vary control . Red light with the DNA-binding domains of enormously on both a day-to-day and triggers a conformational change PIF3 and PIF4, thereby preventing a seasonal basis. In two recent issues in phytochromes, leading to their their transcriptional activity and of Current Biology, Koini et al. [1] and activation. The activated resulting in growth restraint [4,6]. Casson et al. [2] have shown that an phytochromes, in turn, direct In an exciting new study, Koini et al. emerging player in plant responses the degradation of PIFs, with [1] add temperature to the group of to the environment, the basic accompanying effects on the factors that regulate PIF4 activity. helix–loop–helix (bHLH) transcription regulated by these transcription The authors were aiming to find out if factor phytochrome-interacting factor factors (reviewed in [3]). PIFs have been there is a connection between shade 4 (PIF4), has a key role in modulating shown to be important in a range of avoidance and high temperature developmental responses to both developmental processes, such responses, as these stresses lead to light and temperature. as seed germination, seedling very similar phenotypes. Surprisingly, The PIF family of transcription development, hypocotyl elongation they found that a single gene, PIF4,is factors has already been shown to and shade avoidance, that are mainly responsible for hypocotyl and