A central role for regulated protein stability in the control of TFE3 and MITF by nutrients

Nardone, Christopher; Palanski, Brad A.; Scott, Daniel C.; Timms, Richard T.; Barber, Karl W.; Gu, Xin; Mao, Aoyue; Leng, Yumei; Watson, Emma V.; Schulman, Brenda A.; Cole, Philip A.; Elledge, Stephen J.

doi:10.1016/j.molcel.2022.12.013

Cited by 24 publications

(11 citation statements)

References 90 publications

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“…The pooled peptides were dried under reduced pressure using a SpeedVac and resuspended in 30 μl of 0.1% formic acid in water. Liquid chromatography–tandem mass spectrometry data were acquired as reported previously ( 66 ) by injecting 10 μl of resuspended peptide sample.…”

Section: Methodsmentioning

confidence: 99%

The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation

Gu,

Nardone,

Kamitaki

et al. 2023

Science

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Cells use ubiquitin to mark proteins for proteasomal degradation. Although the proteasome also eliminates proteins that are not ubiquitinated, how this occurs mechanistically is unclear. Here, we found that midnolin promoted the destruction of many nuclear proteins, including transcription factors encoded by the immediate-early genes. Diverse stimuli induced midnolin, and its overexpression was sufficient to cause the degradation of its targets by a mechanism that did not require ubiquitination. Instead, midnolin associated with the proteasome via an α helix, used its Catch domain to bind a region within substrates that can form a β strand, and used a ubiquitin-like domain to promote substrate destruction. Thus, midnolin contains three regions that function in concert to target a large set of nuclear proteins to the proteasome for degradation.

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Section: Methodsmentioning

confidence: 99%

The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation

Gu,

Nardone,

Kamitaki

et al. 2023

Science

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“…The C-terminal portion of the predicted fusion protein (TFE3 residues 261-575) retains TFE3’s basic helix-loop-helix (bHLH) transcriptional activation domain. Loss of the N-terminal region of TFE3 may additionally contribute to hyperactive signaling through stabilization of the protein 15 …”

Section: Resultsmentioning

confidence: 99%

“…Loss of the N-terminal region of TFE3 may additionally contribute to hyperactive signaling through stabilization of the protein. 15 The SFPQ::TFEB fusion identified in case 3 is notable for 2 reasons. While TFEB fusions are well-described in a subset of renal carcinomas that typically affect younger patients, this is to our knowledge the first example of a TFEB-rearranged PEComa.…”

Section: Molecular Featuresmentioning

confidence: 97%

Melanotic PEComa

de la Fouchardiere,

Papke,

Pissaloux

et al. 2023

American Journal of Surgical Pathology

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Perivascular epithelioid cell neoplasms (PEComas) are tumors of uncertain cell lineage that show a strong female predominance. Their hallmark is the presence of combined smooth muscle and melanocytic differentiation. In most cases, melanocytic differentiation is detectable only by immunohistochemistry, but there are rare reports of PEComa with extensive melanin accumulation (so-called “melanotic PEComa”). Here we report a clinicopathologic series of 7 melanotic PEComas that occurred across a wide patient age range of 21 to 82 years (median: 41 y) and with a wide anatomic distribution, including 2 cases in the pelvis and 1 case each in the gallbladder, cervix, eyelid, epidural space, and femur. All tumors were heavily pigmented and, like conventional PEComas, were composed of variably sized neoplastic cells with voluminous granular, or less commonly clear, cytoplasm with prominent nucleoli. All tumors expressed HMB45 by immunohistochemistry, and 6 of 7 showed nuclear TFE3 expression. Where tested, tumors were uniformly negative for Mart-1/Melan-A, S100, desmin, and smooth muscle actin. Molecular analysis identified TFE3 gene rearrangement in 5 of 7 cases, 4 of which were demonstrated by fluorescence in situ hybridization and one by whole-exome RNA sequencing which revealed a SFPQ::TFE3 fusion. The one tumor negative for TFE3 by immunohistochemistry was found instead to harbor a SFPQ::TFEB fusion, the first reported example to our knowledge of TFEB fusion in a PEComa. Clinical follow-up was available for 6 of 7 patients (median: 2.5 y: range: 0.75 to 7 y). The patient whose tumor harbored SFPQ::TFEB died of metastatic disease 9 months after diagnosis. The other tumors behaved in an indolent fashion: 4 patients were alive without evidence of disease at the most recent follow-up and 1 patient died of an unrelated cancer 4 years after diagnosis of the melanotic PEComa. Our results expand the morphologic and molecular spectrum of melanotic PEComa, and awareness of this rare but distinctive subtype is important to ensure accurate diagnosis within the broader family of heavily pigmented neoplasms.

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“…As such, identifying the whole substrate landscape of each E3 ligase in different cellular contexts is critical for understanding the various roles and underlying molecular mechanisms of the ubiquitin pathway. Several high‐throughput approaches have been developed to discover E3‐substrate pairs [5–11] . However, each has technical limitations, which can result in a low yield of true positives from initial hits, requiring additional low‐throughput validation.…”

Section: Introductionmentioning

confidence: 99%

“…Several high-throughput approaches have been developed to discover E3-substrate pairs. [5][6][7][8][9][10][11] However, each has technical limitations, which can result in a low yield of true positives from initial hits, requiring additional low-throughput validation. Luciferase reporting assays such as Yeast Two-Hybrid or in vitro ubiquitylation phage display offers high throughput options to find substrates through gene libraries.…”

Section: Introductionmentioning

confidence: 99%

Identifying E3 Ligase Substrates With Quantitative Degradation Proteomics

Jordan

Ordureau

2023

ChemBioChem

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Controlled protein degradation by the ubiquitin‐proteasome pathway is critical for almost all cellular processes. E3 ubiquitin ligases are responsible for targeting proteins for ubiquitylation and subsequent proteasomal degradation with spatial and temporal precision. While studies have revealed various E3‐substrate pairs involved in distinct biological processes, the complete substrate profiles of individual E3 ligases are largely unknown. Here we report a new approach to identify substrates of an E3 ligase for proteasomal degradation using unnatural amino acid incorporation pulse‐chase proteomics (degradomics). Applying this approach, we determine the steady‐state substrates of the C‐terminal to LisH (CTLH) E3 ligase, a multi‐component complex with poorly defined substrates. By comparing the proteome degradation profiles of active and inactive CTLH‐expressing cells, we successfully identify previously known and new potential substrates of CTLH ligase. Altogether, degradomics can comprehensively identify degradation substrates of an E3 ligase, which can be adapted for other E3 ligases in various cellular contexts.

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A central role for regulated protein stability in the control of TFE3 and MITF by nutrients

Cited by 24 publications

References 90 publications

The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation

The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation

Melanotic PEComa

Identifying E3 Ligase Substrates With Quantitative Degradation Proteomics

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