bims-apauto 2023-04-02 papers

Issue of 2023–04–02
four papers selected by
Su Hyun Lee, Harvard University

Nat Commun. 2023 Mar 25. 14(1): 1661

Neutron-encoded diubiquitins to profile linkage selectivity of deubiquitinating enzymes.

Bianca D M van Tol, Bjorn R van Doodewaerd, Guinevere S M Lageveen-Kammeijer, Bas C Jansen, Cami M P Talavera Ormeño, Paul J M Hekking, Aysegul Sapmaz, Robbert Q Kim, Angeliki Moutsiopoulou, David Komander, Manfred Wuhrer, Gerbrand J van der Heden van Noort, Huib Ovaa, Paul P Geurink.

Deubiquitinating enzymes are key regulators in the ubiquitin system and an emerging class of drug targets. These proteases disassemble polyubiquitin chains and many deubiquitinases show selectivity for specific polyubiquitin linkages. However, most biochemical insights originate from studies of single diubiquitin linkages in isolation, whereas in cells all linkages coexist. To better mimick this diubiquitin substrate competition, we develop a multiplexed mass spectrometry-based deubiquitinase assay that can probe all ubiquitin linkage types simultaneously to quantify deubiquitinase activity in the presence of all potential diubiquitin substrates. For this, all eight native diubiquitins are generated and each linkage type is designed with a distinct molecular weight by incorporating neutron-encoded amino acids. Overall, 22 deubiquitinases are profiled, providing a three-dimensional overview of deubiquitinase linkage selectivity over time and enzyme concentration.

DOI: https://doi.org/10.1038/s41467-023-37363-6

EMBO J. 2023 Mar 27. e111241

TFEB-dependent lysosome biogenesis is required for senescence.

Rachel Curnock, Katy Yalci, Johan Palmfeldt, Marja Jäättelä, Bin Liu, Bernadette Carroll.

The accumulation of senescent cells is recognised as a driver of tissue and organismal ageing. One of the gold-standard hallmarks of a senescent cell is an increase in lysosomal content, as measured by senescence-associated β-galactosidase (Senβ-Gal) activity. The lysosome plays a central role in integrating mitogenic and stress cues to control cell metabolism, which is known to be dysregulated in senescence. Despite this, little is known about the cause and consequence of lysosomal biogenesis in senescence. We find here that lysosomes in senescent cells are dysfunctional; they have higher pH, increased evidence of membrane damage and reduced proteolytic capacity. The significant increase in lysosomal content is however sufficient to maintain degradative capacity of the cell to a level comparable to proliferating control cells. We demonstrate that increased nuclear TFEB/TFE3 supports lysosome biogenesis, is a hallmark of multiple forms of senescence and is required for senescent cell survival. TFEB/TFE3 are hypo-phosphorylated and show constitutive nuclear localisation in senescence. Evidence suggests that several pathways may contribute to TFEB/TFE3 dysregulation in senescence.

Keywords: TFEB; autophagy; lysosome; senescence

DOI: https://doi.org/10.15252/embj.2022111241

Biochim Biophys Acta Gene Regul Mech. 2023 Mar 27. pii: S1874-9399(23)00029-9. [Epub ahead of print] 194934

The N-degron pathway: From basic science to therapeutic applications.

Ah Jung Heo, Su Bin Kim, Yong Tae Kwon, Chang Hoon Ji.

The N-degron pathway is a degradative system in which single N-terminal (Nt) amino acids regulate the half-lives of proteins and other biological materials. These determinants, called N-degrons, are recognized by N-recognins that link them to the ubiquitin (Ub)-proteasome system (UPS) or autophagy-lysosome system (ALS). In the UPS, the Arg/N-degron pathway targets the Nt-arginine (Nt-Arg) and other N-degrons to assemble Lys48 (K48)-linked Ub chains by UBR box N-recognins for proteasomal proteolysis. In the ALS, Arg/N-degrons are recognized by the N-recognin p62/SQSTSM-1/Sequestosome-1 to induce cis-degradation of substrates and trans-degradation of various cargoes such as protein aggregates and subcellular organelles. This crosstalk between the UPS and ALP involves reprogramming of the Ub code. Eukaryotic cells developed diverse ways to target all 20 principal amino acids for degradation. Here we discuss the components, regulation, and functions of the N-degron pathways, with an emphasis on the basic mechanisms and therapeutic applications of Arg/N-degrons and N-recognins.

Keywords: Autophagy-lysosome system; E3 ligase; N-recognin; Nt-arginylation; The N-degron pathway; Ubiquitin-proteasome system

DOI: https://doi.org/10.1016/j.bbagrm.2023.194934

Front Oncol. 2023 ;13 1147239

FBXW7 attenuates tumor drug resistance and enhances the efficacy of immunotherapy.

Shimin Chen, Jichun Lin, Jiaojiao Zhao, Qian Lin, Jia Liu, Qiang Wang, Ryan Mui, Leina Ma.

FBXW7 (F-box and WD repeat domain containing 7) is a critical subunit of the Skp1-Cullin1-F-box protein (SCF), acting as an E3 ubiquitin ligase by ubiquitinating targeted protein. Through degradation of its substrates, FBXW7 plays a pivotal role in drug resistance in tumor cells and shows the potential to rescue the sensitivity of cancer cells to drug treatment. This explains why patients with higher FBXW7 levels exhibit higher survival times and more favorable prognosis. Furthermore, FBXW7 has been demonstrated to enhance the efficacy of immunotherapy by targeting the degradation of specific proteins, as compared to the inactivated form of FBXW7. Additionally, other F-box proteins have also shown the ability to conquer drug resistance in certain cancers. Overall, this review aims to explore the function of FBXW7 and its specific effects on drug resistance in cancer cells.

Keywords: E3 ligase; FBXW7; cancer; drug resistance; immunotherapy

DOI: https://doi.org/10.3389/fonc.2023.1147239