ID CD5L_MOUSE Reviewed; 352 AA. AC Q9QWK4; O35300; O35301; Q3TXN5; Q505P6; Q91W05; DT 16-APR-2002, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 3. DT 10-OCT-2018, entry version 135. DE RecName: Full=CD5 antigen-like; DE AltName: Full=Apoptosis inhibitor expressed by macrophages {ECO:0000303|PubMed:9892623}; DE Short=mAIM {ECO:0000303|PubMed:23236605}; DE AltName: Full=Apoptosis inhibitory 6; DE AltName: Full=SP-alpha {ECO:0000303|PubMed:10651944}; DE Flags: Precursor; GN Name=Cd5l; Synonyms=Aim {ECO:0000303|PubMed:9892623}, Api6; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; OC Muroidea; Muridae; Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANTS MET-61; SER-197 AND ARG-205, RP TISSUE SPECIFICITY, AND GLYCOSYLATION. RC STRAIN=BALB/cJ; TISSUE=Thymus; RX PubMed=10651944; DOI=10.1046/j.1365-2567.2000.00903.x; RA Gebe J.A., Llewellyn M.-B.C., Hoggatt H., Aruffo A.; RT "Molecular cloning, genomic organization and cell-binding RT characteristics of mouse Spalpha."; RL Immunology 99:78-86(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION IN APOPTOSIS. RX PubMed=9892623; DOI=10.1084/jem.189.2.413; RA Miyazaki T., Hirokami Y., Matsuhashi N., Takatsuka H., Naito M.; RT "Increased susceptibility of thymocytes to apoptosis in mice lacking RT AIM, a novel murine macrophage-derived soluble factor belonging to the RT scavenger receptor cysteine-rich domain superfamily."; RL J. Exp. Med. 189:413-422(1999). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., RA Davis M.J., Wilming L.G., Aidinis V., Allen J.E., RA Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., RA Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., RA Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., RA Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., RA di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., RA Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., RA Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., RA Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., RA Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., RA Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., RA Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., RA Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., RA Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., RA Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., RA Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., RA Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., RA Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., RA Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., RA Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., RA Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., RA Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., RA Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., RA Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., RA Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., RA Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., RA Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., RA Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., RA Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., RA Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., RA Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-197. RC STRAIN=FVB/N; TISSUE=Liver, and Mammary tumor; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP FUNCTION. RX PubMed=16054063; DOI=10.1016/j.cmet.2005.02.002; RA Arai S., Shelton J.M., Chen M., Bradley M.N., Castrillo A., RA Bookout A.L., Mak P.A., Edwards P.A., Mangelsdorf D.J., Tontonoz P., RA Miyazaki T.; RT "A role for the apoptosis inhibitory factor AIM/Spalpha/Api6 in RT atherosclerosis development."; RL Cell Metab. 1:201-213(2005). RN [6] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FASN. RX PubMed=20519120; DOI=10.1016/j.cmet.2010.04.013; RA Kurokawa J., Arai S., Nakashima K., Nagano H., Nishijima A., RA Miyata K., Ose R., Mori M., Kubota N., Kadowaki T., Oike Y., Koga H., RA Febbraio M., Iwanaga T., Miyazaki T.; RT "Macrophage-derived AIM is endocytosed into adipocytes and decreases RT lipid droplets via inhibition of fatty acid synthase activity."; RL Cell Metab. 11:479-492(2010). RN [7] RP FUNCTION. RX PubMed=21730133; DOI=10.1073/pnas.1101841108; RA Kurokawa J., Nagano H., Ohara O., Kubota N., Kadowaki T., Arai S., RA Miyazaki T.; RT "Apoptosis inhibitor of macrophage (AIM) is required for obesity- RT associated recruitment of inflammatory macrophages into adipose RT tissue."; RL Proc. Natl. Acad. Sci. U.S.A. 108:12072-12077(2011). RN [8] RP FUNCTION. RX PubMed=22579686; DOI=10.1016/j.bbrc.2012.05.018; RA Iwamura Y., Mori M., Nakashima K., Mikami T., Murayama K., Arai S., RA Miyazaki T.; RT "Apoptosis inhibitor of macrophage (AIM) diminishes lipid droplet- RT coating proteins leading to lipolysis in adipocytes."; RL Biochem. Biophys. Res. Commun. 422:476-481(2012). RN [9] RP SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-99 AND ASN-229, LACK OF RP GLYCOSYLATION AT ASN-316, AND MUTAGENESIS OF ASN-99; ASN-229 AND RP ASN-316. RX PubMed=23236605; DOI=10.1016/j.febslet.2012.08.017; RA Mori M., Kimura H., Iwamura Y., Arai S., Miyazaki T.; RT "Modification of N-glycosylation modulates the secretion and lipolytic RT function of apoptosis inhibitor of macrophage (AIM)."; RL FEBS Lett. 586:3569-3574(2012). RN [10] RP FUNCTION. RX PubMed=23562157; DOI=10.1016/j.celrep.2013.03.006; RA Arai S., Maehara N., Iwamura Y., Honda S., Nakashima K., Kai T., RA Ogishi M., Morita K., Kurokawa J., Mori M., Motoi Y., Miyake K., RA Matsuhashi N., Yamamura K., Ohara O., Shibuya A., Wakeland E.K., RA Li Q.Z., Miyazaki T.; RT "Obesity-associated autoantibody production requires AIM to retain the RT immunoglobulin M immune complex on follicular dendritic cells."; RL Cell Rep. 3:1187-1198(2013). RN [11] RP FUNCTION. RX PubMed=26607794; DOI=10.1016/j.cell.2015.11.009; RA Gaublomme J.T., Yosef N., Lee Y., Gertner R.S., Yang L.V., Wu C., RA Pandolfi P.P., Mak T., Satija R., Shalek A.K., Kuchroo V.K., Park H., RA Regev A.; RT "Single-cell genomics unveils critical regulators of Th17 cell RT pathogenicity."; RL Cell 163:1400-1412(2015). RN [12] RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE. RX PubMed=26607793; DOI=10.1016/j.cell.2015.10.068; RA Wang C., Yosef N., Gaublomme J., Wu C., Lee Y., Clish C.B., RA Kaminski J., Xiao S., Meyer Zu Horste G., Pawlak M., Kishi Y., RA Joller N., Karwacz K., Zhu C., Ordovas-Montanes M., Madi A., RA Wortman I., Miyazaki T., Sobel R.A., Park H., Regev A., Kuchroo V.K.; RT "CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell RT pathogenicity."; RL Cell 163:1413-1427(2015). RN [13] RP REVIEW. RX PubMed=26048980; DOI=10.1189/jlb.3RU0215-074R; RA Sanjurjo L., Aran G., Roher N., Valledor A.F., Sarrias M.R.; RT "AIM/CD5L: a key protein in the control of immune homeostasis and RT inflammatory disease."; RL J. Leukoc. Biol. 98:173-184(2015). CC -!- FUNCTION: Secreted protein that acts as a key regulator of lipid CC synthesis: mainly expressed by macrophages in lymphoid and CC inflammed tissues and regulates mechanisms in inflammatory CC responses, such as infection or atherosclerosis (PubMed:26048980). CC Able to inhibit lipid droplet size in adipocytes (PubMed:20519120, CC PubMed:22579686). Following incorporation into mature adipocytes CC via CD36-mediated endocytosis, associates with cytosolic FASN, CC inhibiting fatty acid synthase activity and leading to lipolysis, CC the degradation of triacylglycerols into glycerol and free fatty CC acids (FFA) (PubMed:20519120). CD5L-induced lipolysis occurs with CC progression of obesity: participates in obesity-associated CC inflammation following recruitment of inflammatory macrophages CC into adipose tissues, a cause of insulin resistance and obesity- CC related metabolic disease (PubMed:21730133). Regulation of CC intracellular lipids mediated by CD5L has a direct effect on CC transcription regulation mediated by nuclear receptors ROR-gamma CC (RORC) (PubMed:22579686, PubMed:26607793). Acts as a key regulator CC of metabolic switch in T-helper Th17 cells (PubMed:26607794, CC PubMed:26607793). Regulates the expression of pro-inflammatory CC genes in Th17 cells by altering the lipid content and limiting CC synthesis of cholesterol ligand of RORC, the master transcription CC factor of Th17-cell differentiation (PubMed:26607793). CD5L is CC mainly present in non-pathogenic Th17 cells, where it decreases CC the content of polyunsaturated fatty acyls (PUFA), affecting two CC metabolic proteins MSMO1 and CYP51A1, which synthesize ligands of CC RORC, limiting RORC activity and expression of pro-inflammatory CC genes (PubMed:26607793). Participates in obesity-associated CC autoimmunity via its association with IgM, interfering with the CC binding of IgM to Fcalpha/mu receptor and enhancing the CC development of long-lived plasma cells that produce high-affinity CC IgG autoantibodies (PubMed:23562157). Also acts as an inhibitor of CC apoptosis in macrophages: promotes macrophage survival from the CC apoptotic effects of oxidized lipids in case of atherosclerosis CC (PubMed:9892623, PubMed:16054063). Involved in early response to CC microbial infection against various pathogens by acting as a CC pattern recognition receptor and by promoting autophagy (By CC similarity). {ECO:0000250|UniProtKB:O43866, CC ECO:0000269|PubMed:16054063, ECO:0000269|PubMed:20519120, CC ECO:0000269|PubMed:21730133, ECO:0000269|PubMed:22579686, CC ECO:0000269|PubMed:23562157, ECO:0000269|PubMed:26607793, CC ECO:0000269|PubMed:26607794, ECO:0000269|PubMed:9892623, CC ECO:0000303|PubMed:26048980}. CC -!- SUBUNIT: Interacts with FASN; the interaction is direct CC (PubMed:20519120). Interacts with IgM; protecting CD5L from renal CC excretion and leading to increased CD5L levels in circulating CC blood (PubMed:23562157). {ECO:0000269|PubMed:20519120, CC ECO:0000269|PubMed:23562157}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:20519120, CC ECO:0000269|PubMed:23236605, ECO:0000269|PubMed:9892623}. CC Cytoplasm {ECO:0000269|PubMed:20519120}. Note=Secreted by CC macrophages and circulates in the blood (PubMed:20519120). CC Transported in the cytoplasm via CD36-mediated endocytosis CC (PubMed:20519120). {ECO:0000269|PubMed:20519120}. CC -!- TISSUE SPECIFICITY: Specifically expressed in tissue macrophages CC (PubMed:9892623). Expressed in thymus, liver, spleen and lymph CC nodes (PubMed:10651944). Present in Th17 cells; mainly present in CC non-pathogenic Th17 cells (PubMed:26607793). CC {ECO:0000269|PubMed:10651944, ECO:0000269|PubMed:26607793, CC ECO:0000269|PubMed:9892623}. CC -!- INDUCTION: Transcription is activated by nuclear receptor liver X CC /retinoid X (RXR/LXR). CC -!- PTM: N-glycosylated (PubMed:10651944, PubMed:23236605). N-glycan CC at Asn-99 possesses only alpha2,6-sialylated terminals, while Asn- CC 229 possesses both alpha2,6-sialylated and non-sialylated CC terminals (PubMed:23236605). N-glycosylation increases secretion. CC {ECO:0000269|PubMed:10651944, ECO:0000269|PubMed:23236605}. CC -!- DISRUPTION PHENOTYPE: Mice are apparently healthy under specific CC pathogen-free conditions. However, thymus of mice display much CC fewer thymocytes and CD4/CD8 double-positive (DP) thymocytes are CC more susceptible to apoptosis (PubMed:9892623). Increased CC adipocyte size and adipose tissue mass (PubMed:20519120). Higher CC level of free cholesterol in Th17 cells (PubMed:26607793). CC {ECO:0000269|PubMed:20519120, ECO:0000269|PubMed:26607793, CC ECO:0000269|PubMed:9892623}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF018268; AAB70571.1; -; mRNA. DR EMBL; AF018269; AAB70572.1; -; mRNA. DR EMBL; AF011428; AAD01445.1; -; mRNA. DR EMBL; AK159132; BAE34844.1; -; mRNA. DR EMBL; AK159181; BAE34880.1; -; mRNA. DR EMBL; AK159823; BAE35403.1; -; mRNA. DR EMBL; BC006799; AAH06799.1; -; mRNA. DR EMBL; BC094459; AAH94459.1; -; mRNA. DR CCDS; CCDS17451.1; -. DR RefSeq; NP_033820.2; NM_009690.2. DR UniGene; Mm.6676; -. DR ProteinModelPortal; Q9QWK4; -. DR SMR; Q9QWK4; -. DR BioGrid; 198152; 1. DR IntAct; Q9QWK4; 1. DR MINT; Q9QWK4; -. DR STRING; 10090.ENSMUSP00000015998; -. DR iPTMnet; Q9QWK4; -. DR PhosphoSitePlus; Q9QWK4; -. DR MaxQB; Q9QWK4; -. DR PaxDb; Q9QWK4; -. DR PeptideAtlas; Q9QWK4; -. DR PRIDE; Q9QWK4; -. DR Ensembl; ENSMUST00000015998; ENSMUSP00000015998; ENSMUSG00000015854. DR GeneID; 11801; -. DR KEGG; mmu:11801; -. DR UCSC; uc008psa.2; mouse. DR CTD; 922; -. DR MGI; MGI:1334419; Cd5l. DR eggNOG; ENOG410IKHN; Eukaryota. DR eggNOG; ENOG4110209; LUCA. DR GeneTree; ENSGT00900000140803; -. DR HOGENOM; HOG000290652; -. DR HOVERGEN; HBG031373; -. DR InParanoid; Q9QWK4; -. DR OMA; YHGEDAS; -. DR OrthoDB; EOG091G0DF7; -. DR TreeFam; TF329295; -. DR PRO; PR:Q9QWK4; -. DR Proteomes; UP000000589; Chromosome 3. DR Bgee; ENSMUSG00000015854; Expressed in 75 organ(s), highest expression level in liver. DR CleanEx; MM_CD5L; -. DR Genevisible; Q9QWK4; MM. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IEA:InterPro. DR GO; GO:0005044; F:scavenger receptor activity; IEA:InterPro. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR Gene3D; 3.10.250.10; -; 3. DR InterPro; IPR001190; SRCR. DR InterPro; IPR017448; SRCR-like_dom. DR InterPro; IPR036772; SRCR-like_dom_sf. DR Pfam; PF00530; SRCR; 3. DR PRINTS; PR00258; SPERACTRCPTR. DR SMART; SM00202; SR; 3. DR SUPFAM; SSF56487; SSF56487; 3. DR PROSITE; PS00420; SRCR_1; 1. DR PROSITE; PS50287; SRCR_2; 3. PE 1: Evidence at protein level; KW Apoptosis; Complete proteome; Cytoplasm; Disulfide bond; Glycoprotein; KW Immunity; Inflammatory response; Polymorphism; Reference proteome; KW Repeat; Secreted; Signal. FT SIGNAL 1 21 {ECO:0000255}. FT CHAIN 22 352 CD5 antigen-like. FT /FTId=PRO_0000033226. FT DOMAIN 27 128 SRCR 1. {ECO:0000255|PROSITE- FT ProRule:PRU00196}. FT DOMAIN 141 241 SRCR 2. {ECO:0000255|PROSITE- FT ProRule:PRU00196}. FT DOMAIN 246 348 SRCR 3. {ECO:0000255|PROSITE- FT ProRule:PRU00196}. FT SITE 316 316 Not glycosylated. FT {ECO:0000269|PubMed:23236605}. FT CARBOHYD 99 99 N-linked (GlcNAc...) asparagine. FT {ECO:0000269|PubMed:23236605}. FT CARBOHYD 229 229 N-linked (GlcNAc...) asparagine. FT {ECO:0000269|PubMed:23236605}. FT DISULFID 36 70 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT DISULFID 52 117 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT DISULFID 65 127 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT DISULFID 98 108 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT DISULFID 166 230 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT DISULFID 179 240 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT DISULFID 211 221 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT DISULFID 255 289 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT DISULFID 271 337 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT DISULFID 284 347 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT DISULFID 317 327 {ECO:0000255|PROSITE-ProRule:PRU00196}. FT VARIANT 61 61 V -> M. {ECO:0000269|PubMed:10651944}. FT VARIANT 197 197 N -> S. {ECO:0000269|PubMed:10651944, FT ECO:0000269|PubMed:15489334}. FT VARIANT 205 205 W -> R. {ECO:0000269|PubMed:10651944}. FT MUTAGEN 99 99 N->Q: Decreased glycosylation. FT {ECO:0000269|PubMed:23236605}. FT MUTAGEN 229 229 N->Q: Decreased glycosylation. FT {ECO:0000269|PubMed:23236605}. FT MUTAGEN 316 316 N->Q: Does not affect glycosylation. FT {ECO:0000269|PubMed:23236605}. FT CONFLICT 13 13 S -> N (in Ref. 1; AAB70571). FT {ECO:0000305}. FT CONFLICT 113 113 D -> Y (in Ref. 2; AAD01445). FT {ECO:0000305}. SQ SEQUENCE 352 AA; 38863 MW; 41596AA8012E1AEE CRC64; MAPLFNLMLA ILSIFVGSCF SESPTKVQLV GGAHRCEGRV EVEHNGQWGT VCDDGWDRRD VAVVCRELNC GAVIQTPRGA SYQPPASEQR VLIQGVDCNG TEDTLAQCEL NYDVFDCSHE EDAGAQCENP DSDLLFIPED VRLVDGPGHC QGRVEVLHQS QWSTVCKAGW NLQVSKVVCR QLGCGRALLT YGSCNKNTQG KGPIWMGKMS CSGQEANLRS CLLSRLENNC THGEDTWMEC EDPFELKLVG GDTPCSGRLE VLHKGSWGSV CDDNWGEKED QVVCKQLGCG KSLHPSPKTR KIYGPGAGRI WLDDVNCSGK EQSLEFCRHR LWGYHDCTHK EDVEVICTDF DV //