SKP1-CUL1-F-box protein (SCF) ubiquitin ligases are versatile protein complexes that mediate the ubiquitination of protein substrates. The direct substrate recognition relies on a large family of F-box-domain-containing subunits. One of these substrate receptors is FBXO38, which is encoded by a gene found mutated in families with early-onset distal motor neuronopathy. SCFFBXO38 ubiquitin ligase controls the stability of ZXDB, a nuclear factor associated with the centromeric chromatin protein CENP-B. Loss of FBXO38 in mice results in growth retardation and defects in spermatogenesis characterized by deregulation of the Sertoli cell transcription program and compromised centromere integrity. Moreover, it was reported that SCFFBXO38 mediates the degradation of PD-1, a key immune-checkpoint inhibitor in T cells. Here, we have re-addressed the link between SCFFBXO38 and PD-1 proteolysis. Our data do not support the notion that SCFFBXO38 directly or indirectly controls the abundance and stability of PD-1 in T cells.

Department of Biochemistry and Molecular Pharmacology Howard Hughes Medical Institute Laura and Isaac Perlmutter NYU Cancer Center New York University Grossman School of Medicine New York NY 10016 USA

Faculty of Science Charles University Prague Czech Republic

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Cancer Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

EMBO Rep. 2024 Oct;25(10):4168-4171. doi: 10.1038/s44319-024-00254-y. PubMed

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Akcimen F, Vural A, Durmus H, Cakar A, Houlden H, Parman YG, Nazli Basak A (2019) A novel homozygous FBXO38 variant causes an early-onset distal hereditary motor neuronopathy type IID. J Hum Genet 64:1141–1144 PubMed

Babicki S, Arndt D, Marcu A, Liang Y, Grant JR, Maciejewski A, Wishart DS (2016) Heatmapper: web-enabled heat mapping for all. Nucleic Acids Res 44:W147–W153 PubMed PMC

Belk JA, Yao W, Ly N, Freitas KA, Chen YT, Shi Q, Valencia AM, Shifrut E, Kale N, Yost KE, Duffy CV, Daniel B, Hwee MA, Miao Z, Ashworth A, Mackall CL, Marson A, Carnevale J, Vardhana SA, Satpathy AT (2022) Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence. Cancer Cell 40(7):768–786.e7. 10.1016/j.ccell.2022.06.001 PubMed PMC

Bolognesi B, Lehner B (2018) Reaching the limit. eLife 7:e39804 PubMed PMC

Carrano AC, Eytan E, Hershko A, Pagano M (1999) SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1:193–199 PubMed

de Bie P, Ciechanover A (2011) Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms. Cell Death Differ 18:1393–1402 PubMed PMC

Dibus N, Korinek V, Cermak L (2022a) FBXO38 ubiquitin ligase controls centromere integrity via ZXDA/B stability. Front Cell Dev Biol 10:929288 PubMed PMC

Dibus N, Zobalova E, Monleon MAM, Korinek V, Filipp D, Petrusova J, Sedlacek R, Kasparek P, Cermak L (2022b) FBXO38 ubiquitin ligase controls Sertoli cell maturation. Front Cell Dev Biol 10:914053 PubMed PMC

Dong MB, Wang G, Chow RD, Ye L, Zhu L, Dai X, Park JJ, Kim HR, Errami Y, Guzman CD, Zhou X, Chen KY, Renauer PA, Du Y, Shen J, Lam SZ, Zhou JJ, Lannin DR, Herbst RS, Chen S (2019) Systematic immunotherapy target discovery using genome-scale in vivo CRISPR screens in CD8 T cells. Cell 178(5):1189-1204.e23. 10.1016/j.cell.2019.07.044 PubMed PMC

Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA (2008) Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation. Cell 134:995–1006 PubMed PMC

Glare EM, Divjak M, Bailey MJ, Walters EH (2002) beta-Actin and GAPDH housekeeping gene expression in asthmatic airways is variable and not suitable for normalising mRNA levels. Thorax 57:765–770 PubMed PMC

Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW (2004) Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev 18:2573–2580 PubMed PMC

Mahi NA, Najafabadi MF, Pilarczyk M, Kouril M, Medvedovic M (2019) GREIN: an interactive web platform for re-analyzing GEO RNA-seq data. Sci Rep 9:7580 PubMed PMC

Meng X, Liu X, Guo X, Jiang S, Chen T, Hu Z, Liu H, Bai Y, Xue M, Hu R et al (2018) FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells. Nature 564:130–135 PubMed

Ogando J, Saez ME, Santos J, Nuevo-Tapioles C, Gut M, Esteve-Codina A, Heath S, Gonzalez-Perez A, Cuezva JM, Lacalle RA et al (2019a) Gene Expression Omnibus GSE122149 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE122149) PubMed PMC

Ogando J, Saez ME, Santos J, Nuevo-Tapioles C, Gut M, Esteve-Codina A, Heath S, Gonzalez-Perez A, Cuezva JM, Lacalle RA et al (2019b) PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8(+) T lymphocytes. J Immunother Cancer 7:151 PubMed PMC

Okada M, Chikuma S, Kondo T, Hibino S, Machiyama H, Yokosuka T, Nakano M, Yoshimura A (2017) Blockage of core fucosylation reduces cell-surface expression of PD-1 and promotes anti-tumor immune responses of T cells. Cell Rep 20:1017–1028 PubMed

Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T (2001) PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA 98:13866–13871 PubMed PMC

Pentcheva-Hoang T, Chen L, Pardoll DM, Allison JP (2007) Programmed death-1 concentration at the immunological synapse is determined by ligand affinity and availability. Proc Natl Acad Sci USA 104:17765–17770 PubMed PMC

Reitsma JM, Liu X, Reichermeier KM, Moradian A, Sweredoski MJ, Hess S, Deshaies RJ (2017) Composition and regulation of the cellular repertoire of SCF ubiquitin ligases. Cell 171:1326–1339.e1314 PubMed PMC

Skaar JR, Pagan JK, Pagano M (2013) Mechanisms and function of substrate recruitment by F-box proteins. Nat Rev Mol Cell Biol 14:369–381 PubMed PMC

Skaar JR, Pagan JK, Pagano M (2014) SCF ubiquitin ligase-targeted therapies. Nat Rev Drug Discov 13:889–903 PubMed PMC

Smaldone S, Laub F, Else C, Dragomir C, Ramirez F (2004) Identification of MoKA, a novel F-box protein that modulates Kruppel-like transcription factor 7 activity. Mol Cell Biol 24:1058–1069 PubMed PMC

Sumner CJ, d’Ydewalle C, Wooley J, Fawcett KA, Hernandez D, Gardiner AR, Kalmar B, Baloh RH, Gonzalez M, Zuchner S et al (2013) A dominant mutation in FBXO38 causes distal spinal muscular atrophy with calf predominance. Am J Hum Genet 93:976–983 PubMed PMC

Tit-Oon P, Wonglangka A, Boonkanta K, Ruchirawat M, Fuangthong M, Sasisekharan R, Khongmanee A (2023) Intact mass analysis reveals the novel O-linked glycosylation on the stalk region of PD-1 protein. Sci Rep 13:9631 PubMed PMC

Yukawa M, Jagannathan S, Vallabh S, Kartashov AV, Chen X, Weirauch MT, Barski A (2020a) Gene Expression Omnibus GSE116697 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE116697)

Wu Y, Lin Y, Shen F, Huang R, Zhang Z, Zhou M, Fang Y, Shen J, Fan X (2024) FBXO38 deficiency promotes lysosome-dependent STING degradation and inhibits cGAS-STING pathway activation. Neoplasia 49:100973. 10.1016/j.neo.2024.100973 PubMed PMC

Yukawa M, Jagannathan S, Vallabh S, Kartashov AV, Chen X, Weirauch MT, Barski A (2020b) AP-1 activity induced by co-stimulation is required for chromatin opening during T cell activation. J Exp Med 217:e20182009 PubMed PMC

Zhai X, Liu K, Fang H, Zhang Q, Gao X, Liu F, Zhou S, Wang X, Niu Y, Hong Y et al (2021) Gene Expression Omnibus GSE176310 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE176310)

Zhai X, Liu K, Fang H, Zhang Q, Gao X, Liu F, Zhou S, Wang X, Niu Y, Hong Y et al (2021) Mitochondrial C1qbp promotes differentiation of effector CD8(+) T cells via metabolic-epigenetic reprogramming. Sci Adv 7:eabk0490 PubMed PMC

Zhang Z, Sie B, Chang A, Leng Y, Nardone C, Timms RT, Elledge SJ (2023) Elucidation of E3 ubiquitin ligase specificity through proteome-wide internal degron mapping. Mol Cell 83:3377–3392.e3376 PubMed PMC