E3 ubiquitin ligases catalyze the transfer of an ubiquitin from an E2-ubiquitin conjugate to a target protein. Generally, ubiquitin is transferred via formation of an amide bond to a particular lysine residue of the target protein, but ubiquitylation of cysteine, serine and threonine residues in a few targeted proteins has also been demonstrated (reviewed in McDowell and Philpott 2013, Berndsen and Wolberger 2014). Based on protein homologies, families of E3 ubiquitin ligases have been identified that include RING-type ligases (reviewed in Deshaies et al. 2009, Metzger et al. 2012, Metzger et al. 2014), HECT-type ligases (reviewed in Rotin et al. 2009, Metzger et al. 2012), and RBR-type ligases (reviewed in Dove et al. 2016). A subset of the RING-type ligases participate in CULLIN-RING ligase complexes (CRLs which include SCF complexes, reviewed in Lee and Zhou 2007, Genschik et al. 2013, Skaar et al. 2013, Lee et al. 2014). Some E3-E2 combinations catalyze mono-ubiquitination of the target protein (reviewed in Nakagawa and Nakayama 2015). Other E3-E2 combinations catalyze conjugation of further ubiquitin monomers to the initial ubiquitin, forming polyubiquitin chains. (It may also be possible for some E3-E2 combinations to preassemble polyubiquitin and transfer it as a unit to the target protein.) Ubiquitin contains several lysine (K) residues and a free alpha amino group to which further ubiquitin can be conjugated. Thus different types of polyubiquitin are possible: K11 linked polyubiquitin is observed in endoplasmic reticulum-associated degradation (ERAD), K29 linked polyubiquitin is observed in lysosomal degradation, K48 linked polyubiquitin directs target proteins to the proteasome for degradation, whereas K63 linked polyubiquitin generally acts as a scaffold to recruit other proteins in several cellular processes, notably DNA repair (reviewed in Komander et al. 2009).
View original pathway at Reactome.
Okumoto K, Noda H, Fujiki Y.; ''Distinct modes of ubiquitination of peroxisome-targeting signal type 1 (PTS1) receptor Pex5p regulate PTS1 protein import.''; PubMedEurope PMCScholia
Grou CP, Carvalho AF, Pinto MP, Wiese S, Piechura H, Meyer HE, Warscheid B, Sá-Miranda C, Azevedo JE.; ''Members of the E2D (UbcH5) family mediate the ubiquitination of the conserved cysteine of Pex5p, the peroxisomal import receptor.''; PubMedEurope PMCScholia
MacKay C, Toth R, Rouse J.; ''Biochemical characterisation of the SWI/SNF family member HLTF.''; PubMedEurope PMCScholia
Metzger MB, Hristova VA, Weissman AM.; ''HECT and RING finger families of E3 ubiquitin ligases at a glance.''; PubMedEurope PMCScholia
Ho SR, Lee YJ, Lin WC.; ''Regulation of RNF144A E3 Ubiquitin Ligase Activity by Self-association through Its Transmembrane Domain.''; PubMedEurope PMCScholia
van de Weijer ML, Bassik MC, Luteijn RD, Voorburg CM, Lohuis MA, Kremmer E, Hoeben RC, LeProust EM, Chen S, Hoelen H, Ressing ME, Patena W, Weissman JS, McManus MT, Wiertz EJ, Lebbink RJ.; ''A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation.''; PubMedEurope PMCScholia
Zhang S, Wu W, Wu Y, Zheng J, Suo T, Tang H, Tang J.; ''RNF152, a novel lysosome localized E3 ligase with pro-apoptotic activities.''; PubMedEurope PMCScholia
Lilley BN, Ploegh HL.; ''A membrane protein required for dislocation of misfolded proteins from the ER.''; PubMedEurope PMCScholia
Deng L, Jiang C, Chen L, Jin J, Wei J, Zhao L, Chen M, Pan W, Xu Y, Chu H, Wang X, Ge X, Li D, Liao L, Liu M, Li L, Wang P.; ''The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation.''; PubMedEurope PMCScholia
van den Boomen DJ, Timms RT, Grice GL, Stagg HR, Skødt K, Dougan G, Nathan JA, Lehner PJ.; ''TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I.''; PubMedEurope PMCScholia
Zhang J, Tripathi DN, Jing J, Alexander A, Kim J, Powell RT, Dere R, Tait-Mulder J, Lee JH, Paull TT, Pandita RK, Charaka VK, Pandita TK, Kastan MB, Walker CL.; ''ATM functions at the peroxisome to induce pexophagy in response to ROS.''; PubMedEurope PMCScholia
Foglizzo M, Middleton AJ, Day CL.; ''Structure and Function of the RING Domains of RNF20 and RNF40, Dimeric E3 Ligases that Monoubiquitylate Histone H2B.''; PubMedEurope PMCScholia
Skaar JR, Pagan JK, Pagano M.; ''Mechanisms and function of substrate recruitment by F-box proteins.''; PubMedEurope PMCScholia
Chang CC, Warren DS, Sacksteder KA, Gould SJ.; ''PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import.''; PubMedEurope PMCScholia
Flierman D, Coleman CS, Pickart CM, Rapoport TA, Chau V.; ''E2-25K mediates US11-triggered retro-translocation of MHC class I heavy chains in a permeabilized cell system.''; PubMedEurope PMCScholia
Genschik P, Sumara I, Lechner E.; ''The emerging family of CULLIN3-RING ubiquitin ligases (CRL3s): cellular functions and disease implications.''; PubMedEurope PMCScholia
Ye Y, Meyer HH, Rapoport TA.; ''The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol.''; PubMedEurope PMCScholia
Nordgren M, Francisco T, Lismont C, Hennebel L, Brees C, Wang B, Van Veldhoven PP, Azevedo JE, Fransen M.; ''Export-deficient monoubiquitinated PEX5 triggers peroxisome removal in SV40 large T antigen-transformed mouse embryonic fibroblasts.''; PubMedEurope PMCScholia
Notenboom V, Hibbert RG, van Rossum-Fikkert SE, Olsen JV, Mann M, Sixma TK.; ''Functional characterization of Rad18 domains for Rad6, ubiquitin, DNA binding and PCNA modification.''; PubMedEurope PMCScholia
Lin JR, Zeman MK, Chen JY, Yee MC, Cimprich KA.; ''SHPRH and HLTF act in a damage-specific manner to coordinate different forms of postreplication repair and prevent mutagenesis.''; PubMedEurope PMCScholia
van den Boomen DJ, Lehner PJ.; ''Identifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class I.''; PubMedEurope PMCScholia
Dodt G, Gould SJ.; ''Multiple PEX genes are required for proper subcellular distribution and stability of Pex5p, the PTS1 receptor: evidence that PTS1 protein import is mediated by a cycling receptor.''; PubMedEurope PMCScholia
Zhu B, Zheng Y, Pham AD, Mandal SS, Erdjument-Bromage H, Tempst P, Reinberg D.; ''Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation.''; PubMedEurope PMCScholia
Nakagawa T, Nakayama K.; ''Protein monoubiquitylation: targets and diverse functions.''; PubMedEurope PMCScholia
Huang A, Hibbert RG, de Jong RN, Das D, Sixma TK, Boelens R.; ''Symmetry and asymmetry of the RING-RING dimer of Rad18.''; PubMedEurope PMCScholia
Unk I, Hajdú I, Fátyol K, Hurwitz J, Yoon JH, Prakash L, Prakash S, Haracska L.; ''Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination.''; PubMedEurope PMCScholia
Zhang F, Paramasivam M, Cai Q, Dai X, Wang P, Lin K, Song J, Seidman MM, Wang Y.; ''Arsenite binds to the RING finger domains of RNF20-RNF40 histone E3 ubiquitin ligase and inhibits DNA double-strand break repair.''; PubMedEurope PMCScholia
Rotin D, Kumar S.; ''Physiological functions of the HECT family of ubiquitin ligases.''; PubMedEurope PMCScholia
Plafker SM, Plafker KS, Weissman AM, Macara IG.; ''Ubiquitin charging of human class III ubiquitin-conjugating enzymes triggers their nuclear import.''; PubMedEurope PMCScholia
Hahn MA, Dickson KA, Jackson S, Clarkson A, Gill AJ, Marsh DJ.; ''The tumor suppressor CDC73 interacts with the ring finger proteins RNF20 and RNF40 and is required for the maintenance of histone 2B monoubiquitination.''; PubMedEurope PMCScholia
Dove KK, Stieglitz B, Duncan ED, Rittinger K, Klevit RE.; ''Molecular insights into RBR E3 ligase ubiquitin transfer mechanisms.''; PubMedEurope PMCScholia
Komander D.; ''The emerging complexity of protein ubiquitination.''; PubMedEurope PMCScholia
Ho SR, Mahanic CS, Lee YJ, Lin WC.; ''RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage.''; PubMedEurope PMCScholia
Motegi A, Liaw HJ, Lee KY, Roest HP, Maas A, Wu X, Moinova H, Markowitz SD, Ding H, Hoeijmakers JH, Myung K.; ''Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks.''; PubMedEurope PMCScholia
Unk I, Hajdú I, Fátyol K, Szakál B, Blastyák A, Bermudez V, Hurwitz J, Prakash L, Prakash S, Haracska L.; ''Human SHPRH is a ubiquitin ligase for Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen.''; PubMedEurope PMCScholia
Motegi A, Sood R, Moinova H, Markowitz SD, Liu PP, Myung K.; ''Human SHPRH suppresses genomic instability through proliferating cell nuclear antigen polyubiquitination.''; PubMedEurope PMCScholia
Achar YJ, Balogh D, Neculai D, Juhasz S, Morocz M, Gali H, Dhe-Paganon S, Venclovas Č, Haracska L.; ''Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling.''; PubMedEurope PMCScholia
Zhang F, Yu X.; ''WAC, a functional partner of RNF20/40, regulates histone H2B ubiquitination and gene transcription.''; PubMedEurope PMCScholia
Brophy TM, Raab M, Daxecker H, Culligan KG, Lehmann I, Chubb AJ, Treumann A, Moran N.; ''RN181, a novel ubiquitin E3 ligase that interacts with the KVGFFKR motif of platelet integrin alpha(IIb)beta3.''; PubMedEurope PMCScholia
Kim J, Guermah M, McGinty RK, Lee JS, Tang Z, Milne TA, Shilatifard A, Muir TW, Roeder RG.; ''RAD6-Mediated transcription-coupled H2B ubiquitylation directly stimulates H3K4 methylation in human cells.''; PubMedEurope PMCScholia
Carvalho AF, Pinto MP, Grou CP, Alencastre IS, Fransen M, Sá-Miranda C, Azevedo JE.; ''Ubiquitination of mammalian Pex5p, the peroxisomal import receptor.''; PubMedEurope PMCScholia
Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL.; ''The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol.''; PubMedEurope PMCScholia
Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA.; ''A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol.''; PubMedEurope PMCScholia
Metzger MB, Pruneda JN, Klevit RE, Weissman AM.; ''RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination.''; PubMedEurope PMCScholia
Dickson KA, Cole AJ, Gill AJ, Clarkson A, Gard GB, Chou A, Kennedy CJ, Henderson BR, Australian Ovarian Cancer Study (AOCS), Fereday S, Traficante N, Alsop K, Bowtell DD, deFazio A, Clifton-Bligh R, Marsh DJ.; ''The RING finger domain E3 ubiquitin ligases BRCA1 and the RNF20/RNF40 complex in global loss of the chromatin mark histone H2B monoubiquitination (H2Bub1) in cell line models and primary high-grade serous ovarian cancer.''; PubMedEurope PMCScholia
Yu M, Yang W, Ni T, Tang Z, Nakadai T, Zhu J, Roeder RG.; ''RNA polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA polymerase II.''; PubMedEurope PMCScholia
Lee J, Zhou P.; ''DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase.''; PubMedEurope PMCScholia
Grou CP, Carvalho AF, Pinto MP, Huybrechts SJ, Sá-Miranda C, Fransen M, Azevedo JE.; ''Properties of the ubiquitin-pex5p thiol ester conjugate.''; PubMedEurope PMCScholia
Okumoto K, Misono S, Miyata N, Matsumoto Y, Mukai S, Fujiki Y.; ''Cysteine ubiquitination of PTS1 receptor Pex5p regulates Pex5p recycling.''; PubMedEurope PMCScholia
Sargent G, van Zutphen T, Shatseva T, Zhang L, Di Giovanni V, Bandsma R, Kim PK.; ''PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation.''; PubMedEurope PMCScholia
Pedersen SM, Chan W, Jattani RP, Mackie dS, Pomerantz JL.; ''Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181.''; PubMedEurope PMCScholia
The ubiquitin E3 ligase RNF144A located on endosomal membranes (Ho et al. 2015) binds the catalytic subunit of DNA-dependent protein kinase (PRKDC, DNA-PKcs) and the E2-ubiquitin conjugate UBE2L3:Ubiquitin (UBCH7:Ubiquitin) located in the cytoplasm (Ho et al. 2014).
The ubiquitin E3 ligase RNF144A transfers ubiquitin from the E2-ubiquitin conjugate UBE2L3:Ubiquitin to an unknown residue of PRKDC (DNA-PKcs, the catalytic subunit of DNA-dependent protein kinase) (Ho et al. 2014). RNF144A polyubiquitinates PRKDC with lysine-48 linked ubiquitin, leading to proteasomal degradation of PRKDC. Expression of RNF144A is activated by TP53 (p53) and the degradation of PRKDC caused by RNF144A may be pro-apoptotic (Ho et al. 2014). RNF144A contains a transmembrane domain that localizes RNF144A to endosomal membranes (Ho et al. 2015).
When the cellular concentration of amino acids is low, the ubiquitin E3 ligase RNF152 (Zhang et al. 2010) transfers ubiquitin from the E2-ubiquitin conjugate UBE2N:Ubiquitin to RRAGA (RagA GTPase) (Deng et al. 2015). RNF152 polyubiquitinates RRAGA with lysine-63 linked ubiquitin, which recruits GATOR1, an inhibitor of RRAGA. The inhibition of RRAGA, in turn, inhibits mTORC1 thereby regulating activity of mTORC1 in response to amino acids (Deng et al. 2015). RNF152 is located in the lysosomal membrane and can autoubiquitinate (Zhang et al. 2010).
The ubiquitin E3 ligase RNF152 located in the lysosomal membrane (Zhang et al. 2010) binds GDP-bound RRAGA and the E2-ubiquitin conjugate UBE2N:Ubiquitin prior to ubiquitinating RRAGA (Deng et al. 2015), RNF152, like many E3 ligases, can also autoubiquitinate (Zhang et al. 2010).
The ubiquitin E3 ligase RNF181 interacts with activated (phosphorylated) CARD11, BCL10, and the E2-ubiquitin conjugate (UBE2D1, UBE2D2, UBE2D3, UBE2B, UBE2E1, or UBE2N) (Pedersen et al. 2015).
The ubiquitin E3 ligase RNF181 transfers ubiquitin from the E2-ubiquitin conjugate (UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2B, or UBE2N) to BCL10 (Pedersen et al. 2015). RNF181, which can interact with CARD11, appears to act on BCL10 before BCL10 is recruited to activated (phosphorylated) CARD11. The resulting lysine-48 polyubiquitinated BCL10 is degraded by the proteasome, resulting in attenuation of T cell receptor signaling downstream of CARD11 (Pedersen et al. 2015).
The ubiquitin E3 ligase complex RNF20:RNF40 (also known as Bre1 in Saccharomyces cerevisiae) interacts with the PAF complex and the E2-ubiquitin conjugate UBE2A,B:Ubiquitin (RAD6:Ubiquitin in Saccharomyces cerevisiae) (Zhu et al. 2005, Kim et al. 2009, Hahn et al. 2012, Foglizzo et al. 2016). The complex binds nucleosomal histone H2B after which RNF20:RNF40 monoubiquitinates histone H2B (Zhu et al. 2005, Kim et al. 2009). RNF20:RNF40 also binds WAC, which targets RNF20:RNF40 to the RNA polymerase II complex and promotes monoubiquitination of histone H2B (Zhang and Yu 2011).
The ubiquitin E3 ligase complex RNF20:RNF40 interacts with the PAF complex (Kim et al. 2009) that is associated with RNA polymerase II via WAC (Zhang and Yu 2011) at transcriptionally active genes (Zhe et al. 2005). RNF20:RNF40 monoubiquitinates nucleosomal histone H2B on lysine-120 (lysine-121 of the unprocessed histone H2B) using UBE2A,B:Ubiquitin as the ubiquitin donor (Zhu et al. 2005, Kim et al. 2009, Zhang and Yu 2011, Zhang et al. 2014, Dickson et al. 2016). Monoubiquitination of histone H2B leads to methylation of lysine-4 and lysine-79 of histone H3, marks of active chromatin (Zhu et al. 2005). Arsenite binds the RING domains of RNF20 and RNF40 and inhibits the ubiquitination of histone H2B (Zhang et al. 2014).
In response to a stalled replication fork, SHPRH polyubiquitinates lysine-164 of PCNA that has already been monoubiquitinated on lysine-164 by RAD18:UBE2B (RAD18:RAD6) (Unk et al. 2006, Motegi et al. 2006, Motegi et al. 2008). The ubiquitin donor is the E2 complex UBE2N:UBE2V2 (UBC13:MMS2) containing ubiquitin conjugated to UBE2N. The resulting polyubiquitin chain contains lysine-63 (K63) linkages and appears to change the repair process from translesion synthesis (TLS) to template switching (TS). SHPRH interacts directly with PCNA, RAD18:UBE2B, and UBE2N:UBE2V2.
At stalled replication forks, the E3 ubiquitin ligase SHPRH interacts with PCNA monoubiquitinated at lysine-164 (monoUb-K164-PCNA), the RAD18:UBE2B complex (RAD18:RAD6 complex), and the Ub:UBE2N:UBE2V2 complex (UBC13:MMS2 complex with ubiquitin conjugated to UBC13) (Unk et al. 2006, Motegi et al. 2006, Motegi et al. 2008).
In response to a stalled replication fork, HLTF polyubiquitinates lysine-164 of PCNA that has already been monoubiquitinated on lysine-164 by RAD18:UBE2B (RAD18:RAD6) (Unk et al. 2008, Motegi et al. 2008, MacKay et al. 2009, Achar et al. 2015). The ubiquitin donor is the E2 complex UBE2N:UBE2V2 (UBC13:MMS2) containing ubiquitin conjugated to UBE2N. The resulting polyubiquitin chain contains lysine-63 (K63) linkages and appears to change the repair process from translesion synthesis (TLS) to template switching (TS). HLTF interacts directly with PCNA, RAD18:UBE2B, and UBE2N:UBE2V2. HLTF and SHPRH are not completely redundant: HLTF is involved in repair of DNA lesions created by ultraviolet light while SHPRH is involved in repair of lesions created by methylmethane sulfonate (Lin et al. 2011). Despite the polyubiquitination activity of HLTF, in vivo HLTF appears to increase monoubiquitination of PCNA (Lin et al. 2011).
At stalled replication forks, the E3 ubiquitin ligase HLTF interacts with PCNA monoubiquitinated at lysine-164 (monoUb-K164-PCNA), the RAD18:UBE2B complex (RAD18:RAD6 complex), and the Ub:UBE2N:UBE2V2 complex (UBC13:MMS2 complex with ubiquitin conjugated to UBC13) (Unk et al. 2008, Motegi et al. 2008, MacKay et al. 2009).
The E3 ubiquitin ligase TMEM129 transfers ubiquitin from the E2 ubiquitin conjugases UBE2J2 and UBE2K to a MHC class I heavy chain bound by the human cytomegalovirus US11 protein (van de Weijer et al. 2014, van den Boomen et al. 2014, Flierman et al. 2006, reviewed in van den Boomen and Lehner 2015). TMEM129 is located in the endoplasmic reticulum membrane in a complex containing DERL1, UBE2J2 and UBE2K, VIMP and VCP. After polyubiquitination, MHC class I heavy chain is retrotranslocated by the AAA ATPase VCP to the cytosol (Ye et al. 2001) where it is deglycosylated by NGLYI and degraded by the proteasome (Wiertz et al. 1996). US11 is released after the reaction and, if unable to bind another MHC I heavy chain, US11 is ubiquitinated by the HRD1-SEL1L E3 ubiquitin ligase complex and itself degraded by the proteasome (van den Boomen et al. 2014). This self-regulatory loop allows the amount of US11 in the cell to be buffered against the amount of MHC I molecules.
The human cytomegalovirus US11 protein interacts with a MHC class I heavy chain and recruits the heavy chain to the TMEM129 E3 ubiquitin ligase complex comprising TMEM129, its cognate E2 conjugases UBE2J2 and UBE2K and the VCP complex (VCP:VIMP) via the rhomboid pseudo-protease DERL1 (van de Weijer et al. 2014, van den Boomen et al. 2014, Flierman 2006, Lilley et al. 2004, Ye et al. 2004, Ye et al. 2001).
A RING E3 ubiquitin ligase complex containing PEX10, PEX12, and PEX2 ubiquitinates PEX5L. The PEX2:PEX10:PEX12 complex is believed to bind an activated E2-ubiquitin conjugate (one of Ub:UBE2D1, Ub:UBE2D2, Ub:UBE2D3) and PEX5L in a complex that also contains PEX13 and PEX14 (Chang et al. 1999, Carvalho et al. 2007, Grou et al. 2008, Grou et al. 2009, Okumoto et al. 2011). The short isoform of PEX5, PEX5S, is inferred to undergo the same reaction.
The RING-type E3 ubiquitin ligase sub-complex PEX2:PEX10:PEX12 catalyzes the transfer of ubiquitin from an E2-ubiquitin conjugate (one of Ub:UBE2D1, Ub:UBE2D2, or Ub:UBE2D3) to the cysteine-11 residue of the substrate PEX5L, the peroxisomal matrix protein shuttling receptor (Carvalho et al. 2007; Grou et al. 2008, Okumoto et al. 2011, Sargent et al. 2016, inferred from yeast in Dodt and Gould 1996). The thiol ester bond between ubiquitin and the cysteine residue of PEX5 is unusual among ubiquitin substrates, which usually have isopeptide bonds between ubiquitin and a lysine residue. Monoubiquitination of PEX5 at cysteine-11 is an integral and mandatory step in the PEX5-mediated peroxisomal protein transport pathway; in its absence, PEX5 cannot be extracted from the peroxisomal membrane docking/translocation machinery (the peroxisomal protein translocon), and thus transport of newly synthesized peroxisomal matrix proteins to the organelle matrix stops (Grou et al. 2009). In addition to monoubiquitinating PEX5 during peroxisomal protein import, the PEX2:PEX10:PEX12 complex has also been implicated in pexophagy, a type of selective autophagy targeting peroxisomes. Pexophagy seems to be triggered mainly by ubiquitination of PEX5, which, in this case, can occur either at its cysteine-11 or lysine-209 residues, but ubiquitination of ABCD3 (also known as PMP70) and other peroxisomal membrane proteins may also be involved (Zhang et al. 2015, inferred from mouse in Nordgren et al. 2015, Sargent et al. 2016).
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