| 11560568 | Hsp70 and Hsp90 oppositely regulate TGF-beta signaling through CHIP/Stub1. | Shang Y, etal., Biochem Biophys Res Commun. 2014 Mar 28;446(1):387-92. doi: 10.1016/j.bbrc.2014.02.124. Epub 2014 Mar 5. | Transforming growth factor-beta (TGF-beta) signaling plays an important role in regulation of a wide variety of cellular processes. Canonical TGF-beta signaling is mediated by Smads which were further regulated by several factors. We previously reported that E3 ubiquitin ligase CHIP (carboxyl termi nus of Hsc70-interacting protein, also named Stub1) controlled the sensitivity of TGF-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. Here, we present evidence that Hsp70 and Hsp90 regulate the complex formation of Smad3/CHIP. Furthermore, we observed that over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated CHIP-induced ubiquitination and degradation of Smad3, which finally enhances TGF-beta signaling. In contrast, over-expressed Hsp90 antagonizes CHIP mediated Smad3 ubiquitination and degradation and desensitizes cells in response to TGF-beta signaling. Taken together, our data reveal an opposite role of Hsp70 and Hsp90 in regulating TGF-beta signaling by implicating CHIP-mediated Smad3 ubiquitination and degradation. This study provides a new insight into understanding the regulation of the TGF-beta signaling by chaperones. | 24613385 | 2014-11-01 |
| 10059327 | STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy. | Ferreira JV, etal., Autophagy. 2013 Sep;9(9):1349-66. doi: 10.4161/auto.25190. Epub 2013 Jun 7. | The transcription factor HIF1 is mostly regulated by the oxygen-dependent proteasomal degradation of the labile subunit HIF1A. Recent data showed degradation of HIF1A in the lysosome through chaperone-mediated autophagy (CMA). However the molecular mechanism involved has not been elucidated. This s tudy shows that the KFERQ-like motif, that has been identified in all CMA substrates, is required to mediate the interaction between HIF1A and the chaperone HSPA8. Moreover, mutations in the KFERQ-like motif of HIF1A preclude the interaction with the CMA receptor LAMP2A, thus inhibiting its lysosomal degradation. Importantly, we show for the first time that the ubiquitin ligase STUB1 is required for degradation of HIF1A in the lysosome by CMA. Indeed, mutations in STUB1 that inhibit either the ubiquitin ligase activity or its ability to bind to HSPA8, both prevent degradation of HIF1A by CMA. Moreover, we show that HIF1A binds to and is translocated into intact lysosomes isolated from rat livers. This new pathway for degradation of HIF1A does not depend on the presence of oxygen and is activated in response to nutrient deprivation such that the levels of HIF1A bound to CMA positive lysosomes significantly increase in starved animal livers and the binding of HIF1A to LAMP2A increases in response to serum deprivation. Moreover, excessive degradation of HIF1A by CMA compromises cells' ability to respond to and survive under hypoxia, suggesting that this pathway might be of pathophysiological importance in conditions that combine hypoxia with starvation. | 23880665 | 2013-08-01 |
| 598118586 | Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48). | Genis D, etal., Neurology. 2018 Nov 20;91(21):e1988-e1998. doi: 10.1212/WNL.0000000000006550. Epub 2018 Oct 31. |
OBJECTIVE: To describe a new spinocerebellar ataxia (SCA48) characterized by early cerebellar cognitive-affective syndrome (CCAS) and late-onset SCA.
METHODS: This is a descriptive study of a family that has been followed for more than a decade with periodic neurologic and neuropsychological examinations, MRI, brain SPECT perfusion, and genetic analysis. Whole exome sequencing was performed in 3 affected and 1 unaffected family member and subsequently validated by linkage analysis of chromosome 16p13.3.
RESULTS: Six patients fully developed cognitive-affective and complete motor cerebellar syndrome associated with vermian and hemispheric cerebellar atrophy, suggesting a continuum from a dysexecutive syndrome slowly evolving to a complete and severe CCAS with late truncal ataxia. Three presymptomatic patients showed focal cerebellar atrophy in the vermian, paravermian, and the medial part of cerebellar lobes VI and VII, suggesting that cerebellar atrophy preceded the ataxia, and that the neurodegeneration begins in cerebellar areas related to cognition and emotion, spreading later to the whole cerebellum. Among the candidate variants, only the frameshift heterozygous c.823_824delCT STUB1 (p.L275Dfs*16) pathogenic variant cosegregated with the disease. The p.L275Dfs*16 heterozygous STUB1 pathogenic variant leads to neurodegeneration and atrophy in cognition- and emotion-related cerebellar areas and reinforces the importance of STUB1 in maintaining cognitive cerebellar function.
CONCLUSIONS: We report a heterozygous STUB1 pathogenic genetic variant causing dominant cerebellar ataxia. Since recessive mutations in STUB1 gene have been previously associated with SCAR16, these findings suggest a previously undescribed SCA locus (SCA48; MIM# 618093). | 30381368 | 2018-11-20 |
| 11352993 | Transcription factor RFX1 is ubiquitinated by E3 ligase STUB1 in systemic lupus erythematosus. | Guo Y, etal., Clin Immunol. 2016 Jun 6;169:1-7. doi: 10.1016/j.clim.2016.06.003. | Systemic lupus erythematosus (SLE) is a chronic autoimmune disease caused by complex interactions between genes and the environment. The expression level of transcription factor regulatory factor X 1 (RFX1) is reduced in T cells from SLE patients. RFX1 can regulate epigenetic modifications of CD70 and CD11a and plays an important role in the development of SLE. However, the mechanisms that mediate reduction of RFX1 in SLE are unclear. Here, we demonstrate that RFX1 protein expression can be tightly regulated by polyubiquitination-mediated proteosomal degradation via STIP1 homology and U-box containing protein 1 (STUB1). The E3 ligase STUB1 is upregulated in CD4+T cells of SLE patients compared to healthy subjects. Overexpression of STUB1 in CD4+T cells leads to upregulation of levels of CD70 and CD11a in T cells. The modulation of STUB1 activity may provide a novel therapeutic approach for SLE. | 27283392 | 2016-07-01 |
