Human UFSP1 translated from an upstream near-cognate initiation codon functions as an active UFM1-specific protease

Abstract

Ubiquitin-fold modifier 1 (UFM1) is a recently identified ubiquitin-like posttranslational modification with important biological functions. However, the regulatory mechanisms governing UFM1 modification of target proteins (UFMylation) and the cellular processes controlled by UFMylation remain largely unknown. It has been previously shown that a UFM1-specific protease (UFSP2) mediates the maturation of the UFM1 precursor and drives the de-UFMylation reaction. Furthermore, it has long been thought that UFSP1, an ortholog of UFSP2, is inactive in many organisms, including human, because it lacks an apparent protease domain when translated from the canonical start codon (445AUG). Here, we demonstrate using the combination of site-directed mutagenesis, CRISPR/Cas9–mediated genome editing, and mass spectrometry approaches that translation of human UFSP1 initiates from an upstream near-cognate codon, 217CUG, via eukaryotic translation initiation factor eIF2A-mediated translational initiation rather than from the annotated 445AUG, revealing the presence of a catalytic protease domain containing a Cys active site. Moreover, we show that both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation of target proteins. This study demonstrates that human UFSP1 functions as an active UFM1-specific protease, thus contributing to our understanding of the UFMylation/de-UFMylation process. Ubiquitin-fold modifier 1 (UFM1) is a recently identified ubiquitin-like posttranslational modification with important biological functions. However, the regulatory mechanisms governing UFM1 modification of target proteins (UFMylation) and the cellular processes controlled by UFMylation remain largely unknown. It has been previously shown that a UFM1-specific protease (UFSP2) mediates the maturation of the UFM1 precursor and drives the de-UFMylation reaction. Furthermore, it has long been thought that UFSP1, an ortholog of UFSP2, is inactive in many organisms, including human, because it lacks an apparent protease domain when translated from the canonical start codon (445AUG). Here, we demonstrate using the combination of site-directed mutagenesis, CRISPR/Cas9–mediated genome editing, and mass spectrometry approaches that translation of human UFSP1 initiates from an upstream near-cognate codon, 217CUG, via eukaryotic translation initiation factor eIF2A-mediated translational initiation rather than from the annotated 445AUG, revealing the presence of a catalytic protease domain containing a Cys active site. Moreover, we show that both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation of target proteins. This study demonstrates that human UFSP1 functions as an active UFM1-specific protease, thus contributing to our understanding of the UFMylation/de-UFMylation process. The ubiquitin-fold modifier 1 (UFM1) system is a recently identified ubiquitin-like posttranslational modification with essential biological functions (1Komatsu M. Chiba T. Tatsumi K. Iemura S.I. Tanida I. Okazaki N. et al.A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier.EMBO J. 2004; 23: 1977-1986Crossref PubMed Scopus (219) Google Scholar). Deficiency of this modification leads to embryonic lethality in mice and diseases in humans (2Gerakis Y. Quintero M. Li H. Hetz C. The UFMylation system in proteostasis and beyond.Trends Cell Biol. 2019; 29: 974-986Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). UFM1 is present in nearly all eukaryotic organisms (except fungi) with a similar tertiary structure to ubiquitin. Similar to ubiquitination, the covalent conjugation of UFM1 (UFMylation) to target proteins involves a three-step enzymatic cascade catalyzed sequentially by UFM1-activating enzyme 5 (UBA5, E1), UFM1-conjugating enzyme 1 (UFC1, E2), and UFM1-specific ligase 1 (UFL1, E3) (2Gerakis Y. Quintero M. Li H. Hetz C. The UFMylation system in proteostasis and beyond.Trends Cell Biol. 2019; 29: 974-986Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 3Daniel J. Liebau E. The ufm1 cascade.Cells. 2014; 3: 627-638Crossref PubMed Google Scholar). The UFMylation process is highly conserved in metazoans and plants, implicating its specific roles in multicellular organisms. In human, gene mutations in UFMylation components (UFM1, UFC1, UBA5, DDRGK1, or UFM1-specific protease [UFSP] 2) have been found to be associated with a variety of neurological disorders and skeletal abnormalities (4Nahorski M.S. Maddirevula S. Ishimura R. Alsahli S. Brady A.F. Begemann A. et al.Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.Brain. 2018; 141: 1934-1945Crossref PubMed Scopus (35) Google Scholar, 5Colin E. Daniel J. Ziegler A. Wakim J. Scrivo A. Haack T.B. et al.Biallelic variants in UBA5 reveal that disruption of the UFM1 cascade can result in early-onset encephalopathy.Am. J. Hum. Genet. 2016; 99: 695-703Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 6Egunsola A.T. Bae Y. Jiang M.-M. Liu D.S. Chen-Evenson Y. Bertin T. et al.Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia.J. Clin. Invest. 2017; 127: 1475-1484Crossref PubMed Scopus (26) Google Scholar, 7Di Rocco M. Rusmini M. Caroli F. Madeo A. Bertamino M. Marre-Brunenghi G. et al.Novel spondyloepimetaphyseal dysplasia due to UFSP2 gene mutation.Clin. Genet. 2018; 93: 671-674Crossref PubMed Scopus (13) Google Scholar). Accumulating evidence suggests that UFMylation plays a critical role in diverse cellular processes, including erythrocyte differentiation during embryogenesis (8Tatsumi K. Yamamoto-Mukai H. Shimizu R. Waguri S. Sou Y.-S. Sakamoto A. et al.The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice.Nat. Commun. 2011; 2: 1-7Crossref Scopus (85) Google Scholar, 9Cai Y. Pi W. Sivaprakasam S. Zhu X. Zhang M. Chen J. et al.UFBP1, a key component of the Ufm1 conjugation system, is essential for ufmylation-mediated regulation of erythroid development.PLoS Genet. 2015; 11e1005643Crossref Scopus (76) Google Scholar, 10Zhang M. Zhu X. Zhang Y. Cai Y. Chen J. Sivaprakasam S. et al.RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis.Cell Death Differ. 2015; 22: 1922-1934Crossref PubMed Scopus (88) Google Scholar), endoplasmic reticulum (ER) homeostasis (11Liu J. Wang Y. Song L. Zeng L. Yi W. Liu T. et al.A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability.Nat. Commun. 2017; 8: 1-12Crossref PubMed Scopus (59) Google Scholar, 12Liang J.R. Lingeman E. Luong T. Ahmed S. Muhar M. Nguyen T. et al.A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-resident UFMylation.Cell. 2020; 180: 1160-1177.e20Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar), translational homeostasis (13Walczak C.P. Leto D.E. Zhang L. Riepe C. Muller R.Y. DaRosa P.A. et al.Ribosomal protein RPL26 is the principal target of UFMylation.Proc. Natl. Acad. Sci. U. S. A. 2019; 116: 1299-1308Crossref PubMed Scopus (53) Google Scholar, 14Wang L. Xu Y. Rogers H. Saidi L. Noguchi C.T. Li H. et al.UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis.Cell Res. 2020; 30: 5-20Crossref PubMed Scopus (43) Google Scholar), DNA damage response, and cancer-related signaling pathways (15Wang Z. Gong Y. Peng B. Shi R. Fan D. Zhao H. et al.MRE11 UFMylation promotes ATM activation.Nucleic Acids Res. 2019; 47: 4124-4135Crossref PubMed Scopus (47) Google Scholar, 16Qin B. Yu J. Nowsheen S. Wang M. Tu X. Liu T. et al.UFL1 promotes histone H4 ufmylation and ATM activation.Nat. Commun. 2019; 10: 1-13Crossref PubMed Scopus (48) Google Scholar, 17Yoo H.M. Kang S.H. Kim J.Y. Lee J.E. Seong M.W. Lee S.W. et al.Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.Mol. Cell. 2014; 56: 261-274Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 18Liu J. Guan D. Dong M. Yang J. Wei H. Liang Q. et al.UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.Nat. Cell Biol. 2020; 22: 1056-1063Crossref PubMed Scopus (26) Google Scholar). So far, only one of the E1, E2, and E3 enzymes each of the UFMylation system have been identified, and a handful of substrates have been reported. The regulatory mechanisms governing UFM1 modification of target proteins and the cellular processes controlled by UFMylation remain largely unknown. UFMylation is a reversible process because of UFSPs mediated de-UFMylation reaction (19Kang S.H. Kim G.R. Seong M. Baek S.H. Seol J.H. Bang O.S. et al.Two novel ubiquitin-fold modifier 1 (Ufm1)-specific proteases, UfSP1 and UfSP2.J. Biol. Chem. 2007; 282: 5256-5262Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Although two UFSP genes (UFSP1 and UFSP2) are present in the human genome, it has long been believed that human UFSP1 is inactive or nonfunctional because it lacks a specific protease domain as translated from the annotated 445AUG (2Gerakis Y. Quintero M. Li H. Hetz C. The UFMylation system in proteostasis and beyond.Trends Cell Biol. 2019; 29: 974-986Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 17Yoo H.M. Kang S.H. Kim J.Y. Lee J.E. Seong M.W. Lee S.W. et al.Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.Mol. Cell. 2014; 56: 261-274Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Therefore, UFSP2 has been regarded as the only active protease that mediates UFM1 precursor (pro-UFM1) maturation and de-UFMylation in human cells. Intriguingly, several studies have shown that KO of UFSP2 resulted in significantly increased protein UFMylation in human cells, indicating that other active UFSPs mediate pro-UFM1 maturation in human cells (13Walczak C.P. Leto D.E. Zhang L. Riepe C. Muller R.Y. DaRosa P.A. et al.Ribosomal protein RPL26 is the principal target of UFMylation.Proc. Natl. Acad. Sci. U. S. A. 2019; 116: 1299-1308Crossref PubMed Scopus (53) Google Scholar, 20Ishimura R. Obata M. Kageyama S. Daniel J. Tanaka K. Komatsu M. A novel approach to assess the ubiquitin-fold modifier 1-system in cells.FEBS Lett. 2017; 591: 196-204Crossref PubMed Scopus (16) Google Scholar). Given that only UFSP1 and UFSP2 are present in the human genome, we are naturally concerned about the true identity of UFSP1 in the UFMylation/de-UFMylation process. It has been known for decades that translation can start from codons other than AUG, usually from near-cognate initiation codons, which have a sequence that differs from the AUG codon by one nucleotide (for example, CUG, GUG, and UUG) (21Peabody D.S. Translation initiation at non-AUG triplets in mammalian cells.J. Biol. Chem. 1989; 264: 5031-5035Abstract Full Text PDF PubMed Google Scholar, 22Kearse M.G. Wilusz J.E. Non-AUG translation: a new start for protein synthesis in eukaryotes.Genes Dev. 2017; 31: 1717-1731Crossref PubMed Scopus (158) Google Scholar, 23Ingolia of embryonic stem cells the and of mammalian 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). sequence we identified a of protease catalytic domain upstream of the canonical in human UFSP1 which be from near-cognate In this we that of human UFSP1 is eIF2A-mediated translational and human UFSP1 is a UFSP with in protein the that the near-cognate start codon human UFSP1 protease we two UFSP1 one containing the canonical and the other containing the of the DNA with the The canonical of human UFSP1 is to the with the Intriguingly, we only a specific protein in cells of protein in cells we or and only a protein in cells the of UFMylation significantly by the of or by that of or and and this UFMylation associated with is by the active to that an upstream near-cognate codon, other than the annotated 445AUG codon, for human UFSP1 translation initiation and for the of an active pro-UFM1 the of pro-UFM1 is by the UFSPs to its conserved H.M. J.H. Ubiquitin-fold modifier 1 as a of breast 2015; PubMed Scopus Google Scholar). UFM1 is for conjugation to its target proteins. the of human UFSP1 in pro-UFM1 we a pro-UFM1 or control cells UFSP1, UFSP2, or both UFSP1 and UFSP2, found that the of protein UFMylation significantly with in UFSP1, UFSP2, or KO cells and UFSP2 KO resulted in increased of protein UFMylation in cells and In the of protein UFMylation in UFSP1 KO cells increased or to in the cells and However, UFMylation in KO cells and demonstrate that human UFSP1 is an active UFSP with in protein and UFSP1 and UFSP2 are the only UFSPs in human cells. In eukaryotic cells, initiation codon is the the near-cognate codons identified of embryonic stem cells the and of mammalian 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Liu B. Lee S. B. of translation initiation in mammalian cells at Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). the sequence of human UFSP1 for translation start and found a of codons containing the upstream catalytic to the we have the to codons, 217CUG, and the true initiation we a of mutations each of codons in to which is for human UFSP1 at UFSP1 mutations at or have UFSP1 that codon, the other near-cognate codons, is the translation initiation of human In to the translation initiation we to evidence using mass spectrometry for a cell using system, in which a sequence at the of the human UFSP1 and and The of reveal a of of the human UFSP1, than of the to the canonical The that is the human UFSP1 translation start which the for a when as an start can for M.G. Wilusz J.E. Non-AUG translation: a new start for protein synthesis in eukaryotes.Genes Dev. 2017; 31: 1717-1731Crossref PubMed Scopus (158) Google Scholar). The with UFSP1 a similar result all UFSP1 with the or using or However, our that only one UFSP1 with a to the upstream near-cognate codon of annotated 445AUG and and that UFSP1 only the in human cells. human UFSP1 from 217CUG, we found the of the sequence in the a sequence be for the translation of human The sequence is a plays an important role in translation initiation M. mutations a sequence the AUG codon that modulates translation by eukaryotic Full Text PDF PubMed Scopus Google Scholar, Wang of sequence for translation initiation at non-AUG start Acids Res. 2018; PubMed Scopus Google Scholar). In UFSP1 we that is in an sequence the 445AUG and other near-cognate codons a of UFSP1 with or we found that the sequence can only UFSP1 and protein sequence found that long sequence upstream of is for of human UFSP1 translation as In the sequence and upstream of to be for UFSP1 In to the role of to for UFSP1 we in which the sequence and by a we found the of human UFSP1 with as to that with or found that the sequence and an and the of human UFSP1 significantly by the or that the to sequence plays an important role in human UFSP1 In we that this to sequence upstream is to the that the specific sequence in is essential for human UFSP1 The mechanisms of non-AUG initiation are It has been that plays an important role in translational initiation at the start codon, and protein synthesis at the AUG or start codons Jiang M. S. B. T. et initiates at start codons for protein synthesis and by PubMed Scopus Google Scholar, H. S. Yang J. X. Wang Chen X. et a translated mitochondrial function and 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). example, AUG initiation initiation at the the of human UFSP1 in to in and cells and found that UFSP1 in a A and increased the of UFSP1 and the of UFSP2 and UFMylation by the with or by with only at of the of UFSP1 in both and cells, in UFSP2 and in protein UFMylation and Moreover, human UFSP1 in both in and and and cells. the indispensable role of in translation initiation of human assess the function of UFSP1 in the maturation of the pro-UFM1 and de-UFMylation processes in with UFSP2, we UFMylation/de-UFMylation of the known 1 and that both human UFSP1 and UFSP2 can the UFM1 from In we human UFSP1 and from cells and that human UFSP1 can the to UFM1 in in have to human UFSP1 from human UFSP1 in E. with initiation codon, we have the human UFSP1 protein from E. and that human UFSP1 enzymatic in maturation of pro-UFM1 evidence that human UFSP1, UFSP2, is an active UFM1-specific In our that human UFSP1 catalytic than UFSP2 in de-UFMylation of of UFSP1 mediated protein de-UFMylation than of UFSP2 A and of UFSP1 and UFSP2 are in human and UFSP1 is at a with UFSP2 UFSP2, we found that human UFSP1 is a protein the of UFSP1 and UFSP2 in catalytic and UFMylation in UFSP1 or UFSP2 KO cells, we UFSP2 to be in the of UFSP1 is in the maturation of of UFSP1 and UFSP2 a and reversible process of protein UFMylation/de-UFMylation in cells. In this we that translation of human UFSP1 is from the upstream near-cognate codon in eIF2A-mediated translational rather than the annotated 445AUG codon, an active UFM1-specific The long sequence upstream of plays an important role in the of UFSP1 UFSP2, human UFSP1 functions in both maturation of the pro-UFM1 and de-UFMylation reaction. UFSP2, human UFSP1 at in and have proteins as and have the canonical one or two H. S. Yang J. X. Wang Chen X. et a translated mitochondrial function and 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, C. B. S. F. et of of human factor is in and cells.J. Cell Biol. PubMed Scopus Google Scholar, Chen K. M. Wang L. K. et from the the 2016; PubMed Scopus Google Scholar), human UFSP1 has only the the during we can only a of by which is by the during protein translational initiation M. to the when a AUG codon the Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). human UFSP1 is translated by using near-cognate codon 217CUG, rather than annotated 445AUG Although a sequence the 217CUG, protein (UFSP1 or sequence and The sequence in to upstream of the a role in UFSP1 studies a the of translation and structure stability of sequence the initiation codon G. D. of gene in PubMed Scopus Google Scholar, A. D. A. of a structure the of a translation start 2007; 8: 1-7Crossref PubMed Scopus Google Scholar). Therefore, it is that sequence of human UFSP1 as and for the of translation initiation of plays an important role in translational initiation at non-AUG start other the translation initiation of human UFSP1 is mediated by Given that of leads to a of and is increased during Chen K. M. Wang L. K. et from the the 2016; PubMed Scopus Google Scholar), non-AUG translation is a Although the UFMylation is to homeostasis (8Tatsumi K. Yamamoto-Mukai H. Shimizu R. Waguri S. Sou Y.-S. Sakamoto A. et al.The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice.Nat. Commun. 2011; 2: 1-7Crossref Scopus (85) Google Scholar, 9Cai Y. Pi W. Sivaprakasam S. Zhu X. Zhang M. Chen J. et al.UFBP1, a key component of the Ufm1 conjugation system, is essential for ufmylation-mediated regulation of erythroid development.PLoS Genet. 2015; 11e1005643Crossref Scopus (76) Google Scholar, 10Zhang M. Zhu X. Zhang Y. Cai Y. Chen J. Sivaprakasam S. et al.RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis.Cell Death Differ. 2015; 22: 1922-1934Crossref PubMed Scopus (88) Google Scholar, J. Wang Y. Song L. Zeng L. Yi W. Liu T. et al.A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability.Nat. Commun. 2017; 8: 1-12Crossref PubMed Scopus (59) Google Scholar, 12Liang J.R. Lingeman E. Luong T. Ahmed S. Muhar M. Nguyen T. et al.A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-resident UFMylation.Cell. 2020; 180: 1160-1177.e20Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). Therefore, we that mediated initiation of human UFSP1 as UFSP1 in other a specific regulatory in homeostasis Furthermore, sequence that the Cys protease domain of UFSP1 is conserved organisms from to humans However, the translation initiation of UFSP1 only in in other and that specific regulatory is to the human UFSP1, UFSP1 has a canonical AUG start upstream of Cys protease domain and as an active UFM1-specific protease with (19Kang S.H. Kim G.R. Seong M. Baek S.H. Seol J.H. Bang O.S. et al.Two novel ubiquitin-fold modifier 1 (Ufm1)-specific proteases, UfSP1 and UfSP2.J. Biol. Chem. 2007; 282: 5256-5262Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Although two that UFSP1 at the and functions as of the implicating that UFSP1 plays role in the during C. K. Chen X. et in skeletal Commun. 2020; 1-12Crossref PubMed Scopus Google Scholar, M. B. S. et in skeletal Commun. 2020; PubMed Scopus Google Scholar), and the roles of UFSP1 remain largely unknown. In we identified human UFSP1 as an active UFM1-specific protease in UFMylation/de-UFMylation process. in our understanding of UFMylation/de-UFMylation process in cells. The and of human UFSP1 gene by from The of UFSP1 canonical from annotated codon to codon is to The that the canonical and sequence is to A of sequence of human UFSP1 with UFSP1 or and with the of of the the with specific using in which the sequence and by a of human in the or with or initiation codon using DNA which the initiation codon of the and at the UFSP2 and UBA5 UFC1 DDRGK1, and UFM1 and The in and and in all at the of The target human UFSP1, UFSP2, and UFM1 genes as as control and the of The human and control from UFSP1, DDRGK1 UFSP2, UBA5, UFC1 and and from from of and and are in and cells from the and in with and cell at in a and with to the cells at in the to and of to each using to the with and for of The a and by an in and at target cells cells or in and to The and to the target cells with with the by with for cells or to cell CRISPR/Cas9–mediated as previously A. A. H. D. et genome using of DNA Natl. Acad. Sci. U. S. A. 2017; PubMed Scopus (99) Google Scholar). A DNA sequence the at the of the UFSP1 by to to the A and as for of The is with two and a cells at 5 in a cells with and cells are and as The and by specific the of and a The by UFSP1 or UFSP2 gene cells with of by A of and cells by with 1 for 1 to by and for KO by UFSP1 or UFSP2 cell and UFSP1 and UFSP2 gene cell with cells at from cells by the gene KO cell cells in 1 and containing 1 protease and using by to in and with at and with with identified as an UFMylation H.M. Kang S.H. Kim J.Y. Lee J.E. Seong M.W. Lee S.W. et al.Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.Mol. Cell. 2014; 56: 261-274Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). and for the in UFMylation and de-UFMylation cells with the cells and by in and for Cell with A and containing 1 protease as H.M. Kang S.H. Kim J.Y. Lee J.E. Seong M.W. Lee S.W. et al.Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.Mol. Cell. 2014; 56: 261-274Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). with at the by by of human and E. cell for The and the to 5 of in and at to an of The of human UFSP1 by the of the and The and to by human UFSP1 protein we this for protein of The and of with for human UFSP1 in E. cells. 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S. et al.The in a for mass Acids Res. PubMed Scopus Google Scholar). This The that have of with the of this of the for This by the of and the and and and the and all of the with from and and and the with with with and Liang from and in and of Liang is a in of and of of is the functions and regulatory mechanisms of a recently identified ubiquitin-like posttranslational modification with important biological functions. translation is the key to UFMylation and of Ubiquitin-fold modifier 1 is a ubiquitin-like protein that can be to protein substrates and UFMylation and de-UFMylation are mediated by In it is believed that UFSP2 is the only active Ufm1 protease in Ufm1 maturation and UFSP1 is thought to be Here, Liang et evidence that human UFSP1 is an active Ufm1 an in the human Ufm1 conjugation system and have a only Ufm1 the translation of genes start PDF

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