FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation

被引:5
作者
Barbulescu, Philip [1 ]
Chana, Chetan K. [2 ,3 ]
Wong, Matthew K. [1 ]
Ben Makhlouf, Ines [4 ]
Bruce, Jeffrey P. [5 ]
Feng, Yuqing [1 ]
Keszei, Alexander F. A. [5 ]
Wong, Cassandra [2 ,6 ]
Mohamad-Ramshan, Rukshana [6 ]
McGary, Laura C. [2 ,6 ]
Kashem, Mohammad A. [1 ]
Ceccarelli, Derek F. [3 ]
Orlicky, Stephen [3 ]
Fang, Yifei [1 ]
Kuang, Huihui [7 ]
Mazhab-Jafari, Mohammad [5 ]
Pezo, Rossanna C. [8 ]
Bhagwat, Ashok S. [6 ]
Pugh, Trevor J. [5 ]
Gingras, Anne-Claude [3 ,4 ]
Sicheri, Frank [2 ,3 ,4 ]
Martin, Alberto [1 ]
机构
[1] Univ Toronto, Dept Immunol, Toronto, ON, Canada
[2] Univ Toronto, Dept Biochem, Toronto, ON, Canada
[3] Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada
[4] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada
[5] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada
[6] Wayne State Univ, Dept Chem, Detroit, MI 48202 USA
[7] NYU, Sch Med, Cryo Electron Microscopy Core, New York, NY USA
[8] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada
基金
加拿大创新基金会; 加拿大健康研究院; 美国国家卫生研究院;
关键词
INDUCED CYTIDINE DEAMINASE; SOMATIC HYPERMUTATION; GID COMPLEX; PROTEIN; ACTIVATION; EXPRESSION; SEQUENCE; AID; IDENTIFICATION; RECOGNITION;
D O I
10.1038/s41467-024-52009-x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2). However, FAM72A downregulates UNG2 permitting dUs to persist and trigger SHM and CSR. How FAM72A promotes UNG2 degradation is unknown. Here, we show that FAM72A recruits a C-terminal to LisH (CTLH) E3 ligase complex to target UNG2 for proteasomal degradation. Deficiency in CTLH complex components result in elevated UNG2 and reduced SHM and CSR. Cryo-EM structural analysis reveals FAM72A directly binds to MKLN1 within the CTLH complex to recruit and ubiquitinate UNG2. Our study further suggests that FAM72A hijacks the CTLH complex to promote mutagenesis in cancer. These findings show that FAM72A is an E3 ligase substrate adaptor critical for humoral immunity and cancer development.
引用
收藏
页数:19
相关论文
共 77 条
[1]   Deciphering Signatures of Mutational Processes Operative in Human Cancer [J].
Alexandrov, Ludmil B. ;
Nik-Zainal, Serena ;
Wedge, David C. ;
Campbell, Peter J. ;
Stratton, Michael R. .
CELL REPORTS, 2013, 3 (01) :246-259
[2]   Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 Using Proximity Labeling and Affinity Purification [J].
Aprosoff, Camila M. ;
Dyakov, Boris J. A. ;
Cheung, Vivian H. W. ;
Wong, Cassandra J. ;
Palandra, Mikaela ;
Gingras, Anne-Claude ;
Wyatt, Haley D. M. .
JOURNAL OF PROTEOME RESEARCH, 2023, 22 (06) :1660-1681
[3]  
Bagci H, 2023, bioRxiv, DOI [10.1101/2023.07.20.549906, DOI 10.1101/2023.07.20.549906, 10.1101/2023.07.20.549906]
[4]   Prognostic and Immunological Implications of FAM72A in Pan-Cancer and Functional Validations [J].
Bai, Yuwen ;
Cao, Kui ;
Zhang, Ping ;
Ma, Jianqun ;
Zhu, Jinhong .
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2023, 24 (01)
[5]   Positive-unlabeled convolutional neural networks for particle picking in cryo-electron micrographs [J].
Bepler, Tristan ;
Morin, Andrew ;
Rapp, Micah ;
Brasch, Julia ;
Shapiro, Lawrence ;
Noble, Alex J. ;
Berger, Bonnie .
NATURE METHODS, 2019, 16 (11) :1153-+
[6]   AID and Caspase 8 Shape the Germinal Center Response through Apoptosis [J].
Boulianne, Bryant ;
Rojas, Olga L. ;
Haddad, Dania ;
Zaheen, Ahmad ;
Kapelnikov, Anat ;
Thanh Nguyen ;
Li, Conglei ;
Hakem, Razq ;
Gommerman, Jennifer L. ;
Martin, Alberto .
JOURNAL OF IMMUNOLOGY, 2013, 191 (12) :5840-5847
[7]   Gid9, a second RING finger protein contributes to the ubiquitin ligase activity of the Gid complex required for catabolite degradation [J].
Braun, Bernhard ;
Pfirrmann, Thorsten ;
Menssen, Ruth ;
Hofmann, Kay ;
Scheel, Hartmut ;
Wolf, Dieter H. .
FEBS LETTERS, 2011, 585 (24) :3856-3861
[8]   Precise Temporal Regulation of Post-transcriptional Repressors Is Required for an Orderly Drosophila Maternal-to-Zygotic Transition [J].
Cao, Wen Xi ;
Kabelitz, Sarah ;
Gupta, Meera ;
Yeung, Eyan ;
Lin, Sichun ;
Rammelt, Christiane ;
Ihling, Christian ;
Pekovic, Filip ;
Low, Timothy C. H. ;
Siddiqui, Najeeb U. ;
Cheng, Matthew H. K. ;
Angers, Stephane ;
Smibert, Craig A. ;
Wuehr, Martin ;
Wahle, Elmar ;
Lipshitz, Howard D. .
CELL REPORTS, 2020, 31 (12)
[9]   Mismatch repair co-opted by hypermutation [J].
Cascalho, M ;
Wong, J ;
Steinberg, C ;
Wabl, M .
SCIENCE, 1998, 279 (5354) :1207-1210
[10]   An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme [J].
Ceccarelli, Derek F. ;
Tang, Xiaojing ;
Pelletier, Benoit ;
Orlicky, Stephen ;
Xie, Weilin ;
Plantevin, Veronique ;
Neculai, Dante ;
Chou, Yang-Chieh ;
Ogunjimi, Abiodun ;
Al-Hakim, Abdallah ;
Varelas, Xaralabos ;
Koszela, Joanna ;
Wasney, Gregory A. ;
Vedadi, Masoud ;
Dhe-Paganon, Sirano ;
Cox, Sarah ;
Xu, Shuichan ;
Lopez-Girona, Antonia ;
Mercurio, Frank ;
Wrana, Jeff ;
Durocher, Daniel ;
Meloche, Sylvain ;
Webb, David R. ;
Tyers, Mike ;
Sicheri, Frank .
CELL, 2011, 145 (07) :1075-1087