<scp>UFMylation</scp> of <scp>HRD1</scp> regulates endoplasmic reticulum homeostasis

Luo, Hui; Jiao, Qi‐Bin; Shen, Chuan‐Bin; Gong, Wen‐Yan; Yuan, Jing‐Hua; Liu, Ying‐Ying; Chen, Zhen; Liu, Jiang; Xu, Xiao‐Ling; Cong, Yu‐Sheng; Zhang, Xing‐Wei

doi:10.1096/fj.202300004rrrr

Cited by 6 publications

(3 citation statements)

References 62 publications

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“…Similar to other ubiquitin-like proteins, UFMylation in uences the stability or subcellular localization of substrate proteins (25)(26)(27)(32)(33)(34). Our study revealed that UFMylation impacted the localization of Eg5, without altering its protein stability.…”

Section: Discussionmentioning

confidence: 63%

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Eg5 UFMylation promotes spindle organization during mitosis

Duan,

Li,

Huang

et al. 2024

Preprint

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UFMylation is a highly conserved ubiquitin-like post-translational modification that catalyzes the covalent linkage of UFM1 to its target proteins. This modification plays critical roles in the maintenance of endoplasmic reticulum (ER) proteostasis, DNA damage response, autophagy, and transcriptional regulation. Mutations in UFM1, as well as in its specific E1 enzyme UBA5 and E2 enzyme UFC1, have been genetically linked to microcephaly. Our previous research unveiled the important role of UFMylation in regulating mitosis. However, the underlying mechanisms have remained unclear due to the limited identification of substrates. In this study, we identified Eg5, a motor protein crucial for mitotic spindle assembly and maintenance, as a novel substrate for UFMylation and identified Lys564 as the crucial UFMylation site. UFMylation did not alter its transcriptional level, phosphorylation level, or protein stability, but affected the mono-ubiquitination of Eg5. During mitosis, Eg5 and UFM1 co-localize at the centrosome and spindle apparatus, and defective UFMylation leads to diminished spindle localization of Eg5. Notably, the UFMylation-defective mutant of Eg5 (K564R) displayed shortened or asymmetrical spindles, and suppressed cell proliferation in HeLa cells. Overall, Eg5 UFMylation is essential for proper spindle organization, mitotic progression and cell proliferation.

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Section: Discussionmentioning

confidence: 63%

“…Research into these substrates has revealed a broad spectrum of functions associated with this modi cation. For example, UFMylation of RPL26, RPN1, CYB5R3, and HRD1 maintains the ER proteins during ER stress (31,34,(36)(37)(38). UFMylation regulates tumorigenesis through ASC1, SLC7A11, and PD-L1 (39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Eg5 UFMylation promotes spindle organization during mitosis

Duan,

Li,

Huang

et al. 2024

Preprint

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“…Recent studies have shown that ufmylation is implicated in human diseases, such as hematopoietic diseases ( 16 – 18 ), heart diseases ( 19 ), diabetes ( 20 ), intestinal exocrine diseases ( 21 ), neuronal diseases ( 22 – 25 ), and cancer ( 9 , 12 ). At the cellular level, ufmylation regulates endoplasmic reticulum (ER) stress ( 11 , 26 , 27 ), ER-phagy ( 6 , 28 , 29 ), ribosome- and translocation-associated quality control ( 14 , 30 – 33 ), genomic integrity ( 8 , 15 ), and cell development and death ( 15 , 34 – 36 ). However, virtually nothing is known about its functions and regulation in cellular protein trafficking.…”

Section: Introductionmentioning

confidence: 99%

The ufmylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER

Xu,

Huang,

Bryant

et al. 2024

Sci. Adv.

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Ufmylation is implicated in multiple cellular processes, but little is known about its functions and regulation in protein trafficking. Here, we demonstrate that the genetic depletion of core components of the ufmylation cascade, including ubiquitin-fold modifier 1 (UFM1), UFM1 activation enzyme 5, UFM1-specific ligase 1 (UFL1), UFM1-specific protease 2, and UFM1-binding protein 1 (UFBP1) each markedly inhibits the endoplasmic reticulum (ER)–Golgi transport, surface delivery, and recruitment to COPII vesicles of a subset of G protein–coupled receptors (GPCRs) and UFBP1’s function partially relies on UFM1 conjugation. We also show that UFBP1 and UFL1 interact with GPCRs and UFBP1 localizes at COPII vesicles coated with specific Sec24 isoforms. Furthermore, the UFBP1/UFL1-binding domain identified in the receptors effectively converts non-GPCR protein transport into the ufmylation-dependent pathway. Collectively, these data reveal important functions for the ufmylation system in GPCR recruitment to COPII vesicles, biosynthetic transport, and sorting at ER via UFBP1 ufmylation and interaction directly.

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Bombyx mori UFL1 facilitates BmNPV proliferation by regulating host cell apoptosis through PERK

Zheng,

Meng,

Jiang

et al. 2024

Arch Insect Biochem Physiol

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Ubiquitin‐fold modifier 1 (UFM1) is attached to protein substrates through the sequential activity of an E1 (UBA5)‐E2 (UFC1)‐E3 (UFL1) cascade. UFL1 is the E3 ligase for UFMylation in vertebrates. However, there have been no studies on UFL1 in silkworm to date. In this study, we identified a UFL1 ortholog in Bombyx mori genome. Spatio‐temporal expression profiles showed that BmUFL1 expression was high in the midgut, epidermis, and testis and in the pupa–adult stage. BmUFL1 knockdown inhibited B. mori nucleopolyhedrovirus (BmNPV) proliferation, while BmUFL1 overexpression promoted BmNPV proliferation. Mechanically, protein kinase RNA‐like endoplasmic reticulum kinase (PERK) signaling and cell apoptosis are involved in BmUFL1‐regulated BmNPV proliferation. Overall, these results suggest that BmUFL1 facilitates BmNPV proliferation in silkworm.

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UFMylation of HRD1 regulates endoplasmic reticulum homeostasis

Cited by 6 publications

References 62 publications

Eg5 UFMylation promotes spindle organization during mitosis

Eg5 UFMylation promotes spindle organization during mitosis

The ufmylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER

Bombyx mori UFL1 facilitates BmNPV proliferation by regulating host cell apoptosis through PERK

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