<i>Ufl1</i> deficiency causes kidney atrophy associated with disruption of endoplasmic reticulum homeostasis

You Zhou; Xifu Ye; Chenlu Zhang; Jiabao Wang; Zeyuan Guan; Juzhen Yan; Lu Xu; Ke Wang; Di Guan; Qian Liang; Jian Mao; Junzhi Zhou; Qian Zhang; Xiaoying Wu; Miao Wang; Yu-Sheng Cong; Jiang Liu

doi:10.1016/j.jgg.2021.04.006

Volume 48 Issue 5

May 2021

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2021 > 48(5): 403-410

PDF( 3151 KB)

Ufl1 deficiency causes kidney atrophy associated with disruption of endoplasmic reticulum homeostasis

doi: 10.1016/j.jgg.2021.04.006

a Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Department of Cell Biology and Genetics, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China;
b Department of Nephrology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, China

Funds:

We would like to thank Dr. Haibin Wei, Dr. Ying Wang, and Junyi Wang for the help with experiments. This work was supported by grants from the National Natural Science Foundation of China (31871416, 31730020), the Natural Science Foundation of Zhejiang Province of China (LY18C070001), and the Hangzhou Science and Technology Bureau (20182014B01, 20180533B27).

Received Date: 2020-12-23
Revised Date: 2021-03-29
Accepted Date: 2021-04-01
Publish Date: 2021-05-20

Abstract

Abstract

The UFMylation modification is a novel ubiquitin-like conjugation system, consisting of UBA5 (E1), UFC1 (E2), UFL1 (E3), and the conjugating molecule UFM1. Deficiency in this modification leads to embryonic lethality in mice and diseases in humans. However, the function of UFL1 is poorly characterized. Studies on Ufl1 conditional knockout mice have demonstrated that the deletion of Ufl1 in cardiomyocytes and in intestinal epithelial cells causes heart failure and increases susceptibility to experimentally induced colitis, respectively, suggesting an essential role of UFL1 in the maintenance of the homeostasis in these organs. Yet, its physiological function in other tissues and organs remains completely unknown. In this study, we generate the nephron tubules specific Ufl1 knockout mice and find that the absence of Ufl1 in renal tubular results in kidney atrophy and interstitial fibrosis. In addition, Ufl1 deficiency causes the activation of unfolded protein response and cell apoptosis, which may be responsible for the kidney atrophy and interstitial fibrosis. Collectively, our results have demonstrated the crucial role of UFL1 in regulating kidney function and maintenance of endoplasmic reticulum homeostasis, providing another layer of understanding kidney atrophy.
- UFMylation modification,
- Ufl1,
- Ufl1^fl/flPAX8^Cre/+ mice,
- UPR-PERK signaling pathway,
- ER stress-induced apoptosis,
- Kidney atrophy

These authors contributed equally to this work.

FullText(HTML)

References(26)

References

Brezniceanu, M.L., Lau, C.J., Godin, N., Chenier, I., Duclos, A., Ethier, J., Filep, J.G., Ingelfinger, J.R., Zhang, S.L., Chan, J.S., 2010. Reactive oxygen species promote caspase-12 expression and tubular apoptosis in diabetic nephropathy. J. Am. Soc. Nephrol. 21, 943-954.

Cai, Y., Pi, W., Sivaprakasam, S., Zhu, X., Zhang, M., Chen, J., Makala, L., Lu, C., Wu, J., Teng, Y., et al., 2015. UFBP1, a key component of the Ufm1 conjugation system, is essential for Ufmylation-mediated regulation of erythroid development. PLoS Genet. 11, e1005643.

Cai, Y., Zhu, G., Liu, S., Pan, Z., Quintero, M., Poole, C.J., Lu, C., Zhu, H., Islam, B., Riggelen, J.V., et al., 2019. Indispensable role of the Ubiquitin-fold modifier 1-specific E3 ligase in maintaining intestinal homeostasis and controlling gut inflammation. Cell Discov. 5, 7.

Cappadocia, L., Lima, C.D., 2018. Ubiquitin-like protein conjugation:structures, chemistry, and mechanism. Chem. Rev. 118, 889-918.

Duan, R., Shi, Y., Yu, L., Zhang, G., Li, J., Lin, Y., Guo, J., Wang, J., Shen, L., Jiang, H., et al., 2016. UBA5 mutations cause a new form of autosomal recessive cerebellar ataxia. PLoS One 11, e0149039.

Gowda, S., Desai, P.B., Kulkarni, S.S., Hull, V.V., Math, A.A., Vernekar, S.N., 2010. Markers of renal function tests. N. Am. J. Med. Sci. 2, 170-173.

Komatsu, M., Chiba, T., Tatsumi, K., Iemura, S., Tanida, I., Okazaki, N., Ueno, T., Kominami, E., Natsume, T., Tanaka, K., 2004. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J. 23, 1977-1986.

Lees, G.E., 2004. Early diagnosis of renal disease and renal failure. Vet. Clin. North Am. Small Anim. Pract. 34, 867-885.

Li, J., Yue, G., Ma, W., Zhang, A., Zou, J., Cai, Y., Tang, X., Wang, J., Liu, J., Li, H., et al., 2018. Ufm1-specific ligase Ufl1 regulates endoplasmic reticulum homeostasis and protects against heart failure. Circ. Heart Fail. 11, e004917.

Liu, J., Guan, D., Dong, M., Yang, J., Wei, H., Liang, Q., Song, L., Xu, L., Bai, J., Liu, C., Mao, J., Zhang, Q., Zhou, J., Wu, X., Wang, M., Cong, Y.S., 2020. UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nat. Cell Biol. 22, 1056-1063.

Liu, Y., 2011. Cellular and molecular mechanisms of renal fibrosis. Nat. Rev. Nephrol. 7, 684-696.

Low, K.J., Baptista, J., Babiker, M., Caswell, R., King, C., Ellard, S., Scurr, I., 2019.

Hemizygous UBA5 missense mutation unmasks recessive disorder in a patient with infantile-onset encephalopathy, acquired microcephaly, small cerebellum, movement disorder and severe neurodevelopmental delay. Eur. J. Med. Genet. 62, 97-102.

Lusco, M.A., Fogo, A.B., Najafian, B., Alpers, C.E., 2016. AJKD atlas of renal pathology:tubular atrophy. Am. J. Kidney Dis. 67, e23-e24.

Miller, C., Cai, Y., Patton, T., Graves, S.H., Li, H., Sabbatini, M.E., 2017. RCAD/BiP pathway is necessary for the proper synthesis of digestive enzymes and secretory function of the exocrine pancreas. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G314-G326.

Muona, M., Ishimura, R., Laari, A., Ichimura, Y., Linnankivi, T., Keski-Filppula, R., Herva, R., Rantala, H., Paetau, A., Poyhonen, M., et al., 2016. Biallelic variants in UBA5 link dysfunctional UFM1 ubiquitin-like modifier pathway to severe infantileonset encephalopathy. Am. J. Hum. Genet. 99, 683-694.

Nahorski, M.S., Maddirevula, S., Ishimura, R., Alsahli, S., Brady, A.F., Begemann, A., Mizushima, T., Guzman-Vega, F.J., Obata, M., Ichimura, Y., et al., 2018. Biallelic UFM1 and UFC1 mutations expand the essential role of UFMylation in brain development. Brain 141, 1934-1945.

Neziri, D., Pajenda, S., Amuge, R., Ilhan, A., Wewalka, M., Hormann, G., Zauner, C., Wagner, L., 2016. DDRGK1 in urine indicative of tubular cell injury in intensive care patients with serious infections. J. Nephropathol. 5, 65-71.

Schelling, J.R., 2016. Tubular atrophy in the pathogenesis of chronic kidney disease progression. Pediatr. Nephrol. 31, 693-706.

Seki, M., Nakayama, M., Sakoh, T., Yoshitomi, R., Fukui, A., Katafuchi, E., Tsuda, S., Nakano, T., Tsuruya, K., Kitazono, T., 2019. Blood urea nitrogen is independently associated with renal outcomes in Japanese patients with stage 3-5 chronic kidney disease:a prospective observational study. BMC Nephrol. 20, 115.

Tatsumi, K., Sou, Y.S., Tada, N., Nakamura, E., Iemura, S., Natsume, T., Kang, S.H., Chung, C.H., Kasahara, M., Kominami, E., et al., 2010. A novel type of E3 ligase for the Ufm1 conjugation system. J. Biol. Chem. 285, 5417-5427.

Tatsumi, K., Yamamoto-Mukai, H., Shimizu, R., Waguri, S., Sou, Y.S., Sakamoto, A., Taya, C., Shitara, H., Hara, T., Chung, C.H., et al., 2011. The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice. Nat. Commun. 2, 181.

Watanabe, M., Nakatsuka, A., Murakami, K., Inoue, K., Terami, T., Higuchi, C., Katayama, A., Teshigawara, S., Eguchi, J., Ogawa, D., et al., 2014. Pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathy. PLoS One 9, e92647.

Wu, J., Lei, G., Mei, M., Tang, Y., Li, H., 2010. A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1(DDRGK1) and modulates NF-kappaB signaling. J. Biol. Chem. 285, 15126-15136.

Yoo, H.M., Kang, S.H., Kim, J.Y., Lee, J.E., Seong, M.W., Lee, S.W., Ka, S.H., Sou, Y.S., Komatsu, M., Tanaka, K., et al., 2014. Modification of ASC1 by UFM1 is crucial for ERalpha transactivation and breast cancer development. Mol. Cell 56, 261-274.

Zhang, M., Zhu, X., Zhang, Y., Cai, Y., Chen, J., Sivaprakasam, S., Gurav, A., Pi, W., Makala, L., Wu, J., et al., 2015. RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis. Cell Death Differ. 22, 1922-1934.

Relative Articles

Supplements(0)

Cited By

Proportional views