TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy
The endoplasmic reticulum (ER) stress response and autophagy are important cellular responses that determine cell fate and whose dysregulation is implicated in the perturbation of homeostasis and diseases. Tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) is a pleiotropic stre...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-08-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/9/9/1928 |
| _version_ | 1797556743757103104 |
|---|---|
| author | Hyun Je Kang Eun Jin Yoo Hwan Hee Lee Seung Min An Hyun Park Whaseon Lee-Kwon Soo Youn Choi Hyug Moo Kwon |
| author_facet | Hyun Je Kang Eun Jin Yoo Hwan Hee Lee Seung Min An Hyun Park Whaseon Lee-Kwon Soo Youn Choi Hyug Moo Kwon |
| author_sort | Hyun Je Kang |
| collection | DOAJ |
| description | The endoplasmic reticulum (ER) stress response and autophagy are important cellular responses that determine cell fate and whose dysregulation is implicated in the perturbation of homeostasis and diseases. Tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) is a pleiotropic stress protein that mediates both protective and pathological cellular responses. Here, we examined the role of TonEBP in β-cell survival under ER stress. We found that TonEBP increases β-cell survival under ER stress by enhancing autophagy. The level of TonEBP protein increased under ER stress due to a reduction in its degradation via the ubiquitin–proteasome pathway. In response to ER stress, TonEBP increased autophagosome formations and suppressed the accumulation of protein aggregates and β-cell death. The Rel-homology domain of TonEBP interacted with FIP200, which is essential for the initiation of autophagy, and was required for autophagy and cell survival upon exposure to ER stress. Mice in which <i>TonEBP</i> was specifically deleted in pancreatic endocrine progenitor cells exhibited defective glucose homeostasis and a loss of islet mass. Taken together, these findings demonstrate that TonEBP protects against ER stress-induced β-cell death by enhancing autophagy. |
| first_indexed | 2024-03-10T17:07:15Z |
| format | Article |
| id | doaj.art-c408d514eac843dba6432da9ee3edebc |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T17:07:15Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-c408d514eac843dba6432da9ee3edebc2023-11-20T10:47:25ZengMDPI AGCells2073-44092020-08-0199192810.3390/cells9091928TonEBP Promotes β-Cell Survival under ER Stress by Enhancing AutophagyHyun Je Kang0Eun Jin Yoo1Hwan Hee Lee2Seung Min An3Hyun Park4Whaseon Lee-Kwon5Soo Youn Choi6Hyug Moo Kwon7School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, KoreaSchool of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, KoreaSchool of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, KoreaSchool of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, KoreaSchool of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, KoreaSchool of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, KoreaSchool of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, KoreaSchool of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, KoreaThe endoplasmic reticulum (ER) stress response and autophagy are important cellular responses that determine cell fate and whose dysregulation is implicated in the perturbation of homeostasis and diseases. Tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) is a pleiotropic stress protein that mediates both protective and pathological cellular responses. Here, we examined the role of TonEBP in β-cell survival under ER stress. We found that TonEBP increases β-cell survival under ER stress by enhancing autophagy. The level of TonEBP protein increased under ER stress due to a reduction in its degradation via the ubiquitin–proteasome pathway. In response to ER stress, TonEBP increased autophagosome formations and suppressed the accumulation of protein aggregates and β-cell death. The Rel-homology domain of TonEBP interacted with FIP200, which is essential for the initiation of autophagy, and was required for autophagy and cell survival upon exposure to ER stress. Mice in which <i>TonEBP</i> was specifically deleted in pancreatic endocrine progenitor cells exhibited defective glucose homeostasis and a loss of islet mass. Taken together, these findings demonstrate that TonEBP protects against ER stress-induced β-cell death by enhancing autophagy.https://www.mdpi.com/2073-4409/9/9/1928NFAT5autophagy initiationisletFIP200unfolded protein responseUPR |
| spellingShingle | Hyun Je Kang Eun Jin Yoo Hwan Hee Lee Seung Min An Hyun Park Whaseon Lee-Kwon Soo Youn Choi Hyug Moo Kwon TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy Cells NFAT5 autophagy initiation islet FIP200 unfolded protein response UPR |
| title | TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy |
| title_full | TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy |
| title_fullStr | TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy |
| title_full_unstemmed | TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy |
| title_short | TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy |
| title_sort | tonebp promotes β cell survival under er stress by enhancing autophagy |
| topic | NFAT5 autophagy initiation islet FIP200 unfolded protein response UPR |
| url | https://www.mdpi.com/2073-4409/9/9/1928 |
| work_keys_str_mv | AT hyunjekang tonebppromotesbcellsurvivalundererstressbyenhancingautophagy AT eunjinyoo tonebppromotesbcellsurvivalundererstressbyenhancingautophagy AT hwanheelee tonebppromotesbcellsurvivalundererstressbyenhancingautophagy AT seungminan tonebppromotesbcellsurvivalundererstressbyenhancingautophagy AT hyunpark tonebppromotesbcellsurvivalundererstressbyenhancingautophagy AT whaseonleekwon tonebppromotesbcellsurvivalundererstressbyenhancingautophagy AT sooyounchoi tonebppromotesbcellsurvivalundererstressbyenhancingautophagy AT hyugmookwon tonebppromotesbcellsurvivalundererstressbyenhancingautophagy |