1. Cell Biology
  2. Epidemiology and global health
Download icon

Homo naledi, a new species of the genus Homo from the Dinaledi Chamber, South Africa

  1. Lee R Berger
  2. John Hawks
  3. Darryl J de Ruiter
  4. Steven E Churchill
  5. Peter Schmid
  6. Lucas K Delezene
  7. Tracy L Kivell
  8. Heather M Garvin
  9. Scott A Williams
  10. Jeremy M DeSilva
  11. Matthew M Skinner
  12. Charles M Musiba
  13. Noel Cameron
  14. Trenton W Holliday
  15. William Harcourt-Smith
  16. Rebecca R Ackermann
  17. Markus Bastir
  18. Barry Bogin
  19. Debra Bolter
  20. Juliet Brophy
  21. Zachary D Cofran
  22. Kimberly A Congdon
  23. Andrew S Deane
  24. Mana Dembo
  25. Michelle Drapeau
  26. Marina C Elliott
  27. Elen M Feuerriegel
  28. Daniel Garcia-Martinez
  29. David J Green
  30. Alia Gurtov
  31. Joel D Irish
  32. Ashley Kruger
  33. Myra F Laird
  34. Damiano Marchi
  35. Marc R Meyer
  36. Shahed Nalla
  37. Enquye W Negash
  38. Caley M Orr
  39. Davorka Radovcic
  40. Lauren Schroeder
  41. Jill E Scott
  42. Zachary Throckmorton
  43. Caroline VanSickle
  44. Christopher S Walker
  45. Pianpian Wei
  46. Bernhard Zipfel
  1. University of the Witwatersrand, South Africa
  2. University of Wisconsin-Madison, United States
  3. Texas A&M University, United States
  4. Duke University, United States
  5. University of Zurich, Switzerland
  6. University of Arkansas, United States
  7. University of Kent, United Kingdom
  8. Max Planck Institute for Evolutionary Anthropology, Germany
  9. Mercyhurst University, United States
  10. New York University, United States
  11. New York Consortium in Evolutionary Primatology, United States
  12. Dartmouth College, United States
  13. University of Colorado Denver, United States
  14. Loughborough University, United Kingdom
  15. Tulane University, United States
  16. Lehman College, United States
  17. American Museum of Natural History, United States
  18. University of Cape Town, South Africa
  19. Museo Nacional de Ciencias Naturales, Spain
  20. Modesto Junior College, United States
  21. Louisiana State University, United States
  22. Nazarbayev University, Kazakhstan
  23. University of Missouri, United States
  24. University of Kentucky College of Medicine, United States
  25. Simon Fraser University, Canada
  26. Université de Montréal, Canada
  27. Australian National University, Australia
  28. Biology Department, Universidad Autònoma de Madrid, Spain
  29. Midwestern University, United States
  30. Liverpool John Moores University, United Kingdom
  31. University of Pisa, Italy
  32. Chaffey College, United States
  33. University of Johannesburg, South Africa
  34. George Washington University, United States
  35. University of Colorado School of Medicine, United States
  36. Croatian Natural History Museum, Croatia
  37. University of Iowa, United States
  38. Lincoln Memorial University, United States
  39. Smithsonian Institution, United States
  40. Institute of Vertebrate Paleontology and Paleoanthropology, China
Research article
Cite this article as: eLife 2016;5:e16370 doi: 10.7554/eLife.16370

Abstract

It is well established that learning can occur without external feedback, yet normative reinforcement learning theories have difficulties explaining such instances of learning. Here, we propose that human observers are capable of generating their own feedback signals by monitoring internal decision variables. We investigated this hypothesis in a visual perceptual learning task using fMRI and confidence reports as a measure for this monitoring process. Employing a novel computational model in which learning is guided by confidence-based reinforcement signals, we found that mesolimbic brain areas encoded both anticipation and prediction error of confidence—in remarkable similarity to previous findings for external reward-based feedback. We demonstrate that the model accounts for choice and confidence reports and show that the mesolimbic confidence prediction error modulation derived through the model predicts individual learning success. These results provide a mechanistic neurobiological explanation for learning without external feedback by augmenting reinforcement models with confidence-based feedback.

Charts

  • 547
    Views
  • 320
    Downloads
  • 89
    Citations

Introduction

TNF Receptor Associated Factor 2 (TRAF2) is an adaptor protein that transduces signals following ligation of certain cytokine receptors including those binding TNF. It was first identified together with TRAF1 as a component of TNF receptor-2 and then TNF receptor-1 (TNFR1) signalling complexes (Rothe et al., 1994; Shu et al., 1996). TRAF2, like most other TRAFs, contains a RING domain, several zinc fingers, a TRAF-N, and a conserved TRAF-C domain which is responsible for oligomerisation and receptor binding through its MATH region (Takeuchi et al., 1996; Uren and Vaux, 1996).

RING domains are nearly always associated with ubiquitin E3 ligase activity (Shi and Kehrl, 2003) and TRAF2 can promote ubiquitylation of RIPK1 in TNFR1 signalling complexes (TNFR1-SC) (Wertz et al., 2004). However TRAF2 recruits E3 ligases such as cIAPs to TNFR1-SC and these have also been shown to be able to ubiquitylate RIPK1 and regulate TNF signalling (Dynek et al., 2010; Mahoney et al., 2008; Varfolomeev et al., 2008; Vince et al., 2009). This makes it difficult to unambiguously determine the role of the E3 ligase activity of TRAF2.

Activation of JNK and NF-κB by TNF is reduced in cells from Traf2-/- mice while only JNK signalling was affected in lymphocytes from transgenic mice that express a dominant negative (DN) form of TRAF2 that lacks the RING domain (Lee et al., 1997; Yeh et al., 1997). Traf2-/-Traf5-/- mouse embryonic fibroblasts (MEFs) have a pronounced defect in activation of NF-κB by TNF, suggesting that absence of TRAF2 can be compensated by TRAF5 (Tada et al., 2001). Although activation of NF-κB was restored in Traf2-/-Traf5-/- cells by re-expression of wild type TRAF2, it was not restored when the cells were reconstituted with TRAF2 point mutants that could not bind cIAPs (Vince et al., 2009; Zhang et al., 2010). These data, together with a wealth of different lines of evidence showing that cIAPs are critical E3 ligases required for TNF-induced canonical NF-κB (Blackwell et al., 2013; Haas et al., 2009; Silke, 2011), support the idea that the main function of TRAF2 in TNF-induced NF-κB is to recruit cIAPs to the TNFR1-SC. However, it remains possible that the RING of TRAF2 plays another function, such as in activating JNK and protecting cells from TNF-induced cell death (Vince et al., 2009; Zhang et al., 2010). Furthermore it has been shown that TRAF2 can K48-ubiquitylate caspase-8 to set the threshold for TRAIL or Fas induced cell death (Gonzalvez et al., 2012). Moreover, TRAF2 inhibits non-canonical NF-κB signalling (Grech et al., 2004; Zarnegar et al., 2008) and this function requires the RING domain of TRAF2 to induce proteosomal degradation of NIK (Vince et al., 2009). However, structural and in vitro analyses indicate that, unlike TRAF6, the RING domain of TRAF2 is unable to bind E2 conjugating enzymes (Yin et al., 2009), and is therefore unlikely to have intrinsic E3 ligase activity.

Sphingosine-1-phosphate (S1P) is a pleiotropic sphingolipid mediator that regulates proliferation, differentiation, cell trafficking and vascular development (Pitson, 2011). S1P is generated by sphingosine kinase 1 and 2 (SPHK1 and SPHK2) (Kohama et al., 1998; Liu et al., 2000). Extracellular S1P mainly acts by binding to its five G protein-coupled receptors S1P1-5 (Hla and Dannenberg, 2012). However, some intracellular roles have been suggested for S1P, including the blocking of the histone deacetylases, HDAC1/2 (Hait et al., 2009) and the induction of apoptosis through interaction with BAK and BAX (Chipuk et al., 2012).

Recently, it was suggested that the RING domain of TRAF2 requires S1P as a co-factor for its E3 ligase activity (Alvarez et al., 2010). Alvarez and colleagues proposed that SPHK1 but not SPHK2 is activated by TNF and phosphorylates sphingosine to S1P which in turn binds to the RING domain of TRAF2 and serves as an essential co-factor that was missing in the experiments of Yin et al. Alvarez and colleagues, observed that in the absence of SPHK1, TNF-induced NF-κB activation was completely abolished.

Although we know a lot about TRAF2, there are still important gaps particularly with regard to cell type specificity and in vivo function of TRAF2. Moreover, despite the claims that SPHK1 and its product, S1P, are required for TRAF2 to function as a ubiquitin ligase, the responses of Traf2-/- and Sphk1-/- cells to TNF were not compared. Therefore, we undertook an analysis of TRAF2 and SPHK1 function in TNF signalling in a number of different tissues.

Surprisingly, we found that neither TRAF2 nor SPHK1 are required for TNF mediated canonical NF-κB and MAPK signalling in macrophages. However, MEFs, murine dermal fibroblasts (MDFs) and keratinocytes required TRAF2 but not SPHK1 for full strength TNF signalling. In these cell types, absence of TRAF2 caused a delay in TNF-induced activation of NF-κB and MAPK, and sensitivity to killing by TNF was increased. Absence of TRAF2 in keratinocytes in vivo resulted in psoriasis-like epidermal hyperplasia and skin inflammation. Unlike TNF-dependent genetic inflammatory skin conditions, such as IKK2 epidermal knock-out (Pasparakis et al., 2002) and the cpdm mutant (Gerlach et al., 2011), the onset of inflammation was only delayed, and not prevented by deletion of TNF. This early TNF-dependent inflammation is caused by excessive apoptotic but not necroptotic cell death and could be prevented by deletion of Casp8. We observed constitutive activation of NIK and non-canonical NF-κB in Traf2-/- keratinocytes which caused production of inflammatory cytokines and chemokines. We were able to reverse this inflammatory phenotype by simultaneously deleting both Tnf and Nfkb2 genes. Our results highlight the important role TRAF2 plays to protect keratinocytes from cell death and to down-regulate inflammatory responses and support the idea that intrinsic defects in keratinocytes can initiate psoriasis-like skin inflammation.

TNF Receptor Associated Factor 2 (TRAF2) is an adaptor protein that transduces signals following ligation of certain cytokine receptors including those binding TNF. It was first identified together with TRAF1 as a component of TNF receptor-2 and then TNF receptor-1 (TNFR1) signalling complexes (Rothe et al., 1994; Shu et al., 1996). TRAF2, like most other TRAFs, contains a RING domain, several zinc fingers, a TRAF-N, and a conserved TRAF-C domain which is responsible for oligomerisation and receptor binding through its MATH region (Takeuchi et al., 1996; Uren and Vaux, 1996).

I am a nested fragment

RING domains are nearly always associated with ubiquitin E3 ligase activity (Shi and Kehrl, 2003) and TRAF2 can promote ubiquitylation of RIPK1 in TNFR1 signalling complexes (TNFR1-SC) (Wertz et al., 2004). However TRAF2 recruits E3 ligases such as cIAPs to TNFR1-SC and these have also been shown to be able to ubiquitylate RIPK1 and regulate TNF signalling (Dynek et al., 2010; Mahoney et al., 2008; Varfolomeev et al., 2008; Vince et al., 2009). This makes it difficult to unambiguously determine the role of the E3 ligase activity of TRAF2.

Activation of JNK and NF-κB by TNF is reduced in cells from Traf2-/- mice while only JNK signalling was affected in lymphocytes from transgenic mice that express a dominant negative (DN) form of TRAF2 that lacks the RING domain (Lee et al., 1997; Yeh et al., 1997). Traf2-/-Traf5-/- mouse embryonic fibroblasts (MEFs) have a pronounced defect in activation of NF-κB by TNF, suggesting that absence of TRAF2 can be compensated by TRAF5 (Tada et al., 2001). Although activation of NF-κB was restored in Traf2-/-Traf5-/- cells by re-expression of wild type TRAF2, it was not restored when the cells were reconstituted with TRAF2 point mutants that could not bind cIAPs (Vince et al., 2009; Zhang et al., 2010). These data, together with a wealth of different lines of evidence showing that cIAPs are critical E3 ligases required for TNF-induced canonical NF-κB (Blackwell et al., 2013; Haas et al., 2009; Silke, 2011), support the idea that the main function of TRAF2 in TNF-induced NF-κB is to recruit cIAPs to the TNFR1-SC. However, it remains possible that the RING of TRAF2 plays another function, such as in activating JNK and protecting cells from TNF-induced cell death (Vince et al., 2009; Zhang et al., 2010). Furthermore it has been shown that TRAF2 can K48-ubiquitylate caspase-8 to set the threshold for TRAIL or Fas induced cell death (Gonzalvez et al., 2012). Moreover, TRAF2 inhibits non-canonical NF-κB signalling (Grech et al., 2004; Zarnegar et al., 2008) and this function requires the RING domain of TRAF2 to induce proteosomal degradation of NIK (Vince et al., 2009). However, structural and in vitro analyses indicate that, unlike TRAF6, the RING domain of TRAF2 is unable to bind E2 conjugating enzymes (Yin et al., 2009), and is therefore unlikely to have intrinsic E3 ligase activity.

Sphingosine-1-phosphate (S1P) is a pleiotropic sphingolipid mediator that regulates proliferation, differentiation, cell trafficking and vascular development (Pitson, 2011). S1P is generated by sphingosine kinase 1 and 2 (SPHK1 and SPHK2) (Kohama et al., 1998; Liu et al., 2000). Extracellular S1P mainly acts by binding to its five G protein-coupled receptors S1P1-5 (Hla and Dannenberg, 2012). However, some intracellular roles have been suggested for S1P, including the blocking of the histone deacetylases, HDAC1/2 (Hait et al., 2009) and the induction of apoptosis through interaction with BAK and BAX (Chipuk et al., 2012).

Recently, it was suggested that the RING domain of TRAF2 requires S1P as a co-factor for its E3 ligase activity (Alvarez et al., 2010). Alvarez and colleagues proposed that SPHK1 but not SPHK2 is activated by TNF and phosphorylates sphingosine to S1P which in turn binds to the RING domain of TRAF2 and serves as an essential co-factor that was missing in the experiments of Yin et al. Alvarez and colleagues, observed that in the absence of SPHK1, TNF-induced NF-κB activation was completely abolished.

I am a nested frag

Although we know a lot about TRAF2, there are still important gaps particularly with regard to cell type specificity and in vivo function of TRAF2. Moreover, despite the claims that SPHK1 and its product, S1P, are required for TRAF2 to function as a ubiquitin ligase, the responses of Traf2-/- and Sphk1-/- cells to TNF were not compared. Therefore, we undertook an analysis of TRAF2 and SPHK1 function in TNF signalling in a number of different tissues.

Surprisingly, we found that neither TRAF2 nor SPHK1 are required for TNF mediated canonical NF-κB and MAPK signalling in macrophages. However, MEFs, murine dermal fibroblasts (MDFs) and keratinocytes required TRAF2 but not SPHK1 for full strength TNF signalling. In these cell types, absence of TRAF2 caused a delay in TNF-induced activation of NF-κB and MAPK, and sensitivity to killing by TNF was increased. Absence of TRAF2 in keratinocytes in vivo resulted in psoriasis-like epidermal hyperplasia and skin inflammation. Unlike TNF-dependent genetic inflammatory skin conditions, such as IKK2 epidermal knock-out (Pasparakis et al., 2002) and the cpdm mutant (Gerlach et al., 2011), the onset of inflammation was only delayed, and not prevented by deletion of TNF. This early TNF-dependent inflammation is caused by excessive apoptotic but not necroptotic cell death and could be prevented by deletion of Casp8. We observed constitutive activation of NIK and non-canonical NF-κB in Traf2-/- keratinocytes which caused production of inflammatory cytokines and chemokines. We were able to reverse this inflammatory phenotype by simultaneously deleting both Tnf and Nfkb2 genes. Our results highlight the important role TRAF2 plays to protect keratinocytes from cell death and to down-regulate inflammatory responses and support the idea that intrinsic defects in keratinocytes can initiate psoriasis-like skin inflammation.

https://doi.org/10.7554/eLife.16370

Article download links

A three part list of links to download the article, or parts of the article, in various formats.

Downloads (links to download the article or parts of the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)