UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD

Lin, Brian C.; Higgins, Nicole; Phung, Trong H.; Monteiro, Mervyn J.

doi:10.1111/febs.16129

Cited by 23 publications

(17 citation statements)

References 190 publications

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“…In contrast, K63‐ and M1‐linked polyUb are typically involved in nonproteolytic signaling pathways such as cargo sorting, DNA repair, NF‐Kβ signaling, and autophagy (Olzmann et al , 2007 ; Haglund & Dikic, 2012 ; Linares et al , 2013 ; Piper et al , 2014 ; Sun et al , 2018 ). UBQLN2 has known affiliations with the proteasome, autophagy receptors (LC3) and cargo sorting adaptor proteins (epsin 1 and 2) (Zheng et al , 2020 ; Lin et al , 2021 ). We showed that UBQLN2 LLPS can be rapidly modulated by changes in cellular signaling (e.g., formation of K63‐linked chains or ubiquitinated substrates, Fig 6 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights into enhancement or inhibition of phase separation by different polyubiquitin chains

et al. 2022

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Ubiquitin‐binding shuttle UBQLN2 mediates crosstalk between proteasomal degradation and autophagy, likely via interactions with K48‐ and K63‐linked polyubiquitin chains, respectively. UBQLN2 comprises self‐associating regions that drive its homotypic liquid–liquid phase separation (LLPS). Specific interactions between one of these regions and ubiquitin inhibit UBQLN2 LLPS. Here, we show that, unlike ubiquitin, the effects of multivalent polyubiquitin chains on UBQLN2 LLPS are highly dependent on chain types. Specifically, K11‐Ub4 and K48‐Ub4 chains generally inhibit UBQLN2 LLPS, whereas K63‐Ub4, M1‐Ub4 chains, and a designed tetrameric ubiquitin construct significantly enhance LLPS. We demonstrate that these opposing effects stem from differences in chain conformations but not in affinities between chains and UBQLN2. Chains with extended conformations and increased accessibility to the ubiquitin‐binding surface promote UBQLN2 LLPS by enabling a switch between homotypic to partially heterotypic LLPS that is driven by both UBQLN2 self‐interactions and interactions between multiple UBQLN2 units with each polyubiquitin chain. Our study provides mechanistic insights into how the structural and conformational properties of polyubiquitin chains contribute to heterotypic LLPS with ubiquitin‐binding shuttles and adaptors.

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Section: Discussionmentioning

confidence: 99%

Mechanistic insights into enhancement or inhibition of phase separation by different polyubiquitin chains

et al. 2022

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“…In contrast, K63- and M1-linked polyUb are typically involved in non-proteolytic signaling pathways such as cargo sorting, DNA repair, NF-Kβ signaling, and autophagy (Haglund and Dikic, 2012; Linares et al, 2013; Olzmann et al, 2007; Piper et al, 2014; Sun et al, 2018). UBQLN2 has known affiliations with the proteasome, autophagy receptors (LC3) and cargo sorting adaptor proteins (epsin 1 and 2) (Lin et al, 2021; Zheng et al, 2020). We showed that UBQLN2 LLPS can be rapidly modulated by changes in cellular signaling (e.g.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights into the enhancement or inhibition of phase separation by polyubiquitin chains of different lengths or linkages

Dao

Yang

Presti

et al. 2021

Preprint

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SummaryUbiquitin-binding shuttle UBQLN2 mediates crosstalk between proteasomal degradation and autophagy, likely via interactions with K48- and K63-linked polyubiquitin chains, respectively. UBQLN2 is recruited to stress granules in cells and undergoes liquid-liquid phase separation (LLPS) in vitro. However, interactions with ubiquitin or multivalent K48-linked chains eliminate LLPS. Here, we found that, although some polyubiquitin chain types (K11-Ub4 and K48-Ub4) did generally inhibit UBQLN2 LLPS, others (K63-Ub4, M1-Ub4 and a designed tetrameric ubiquitin construct) significantly enhanced LLPS. Using nuclear magnetic resonance (NMR) spectroscopy and complementary biophysical techniques, we demonstrated that these opposing effects stem from differences in chain conformations, but not in affinities between chains and UBQLN2. Chains with extended conformations and increased accessibility to the ubiquitin binding surface significantly promoted UBQLN2 LLPS by enabling a switch between homotypically to partially heterotypically-driven phase separation. Our study provides mechanistic insights into how the structural and conformational properties of polyubiquitin chains contribute to heterotypic phase separation with ubiquitin-binding shuttles and adaptors.HighlightsUbiquitin or short polyubiquitin chains bind to phase separation-driving stickers on UBQLN2 and inhibit its phase separation whereas longer chains provide the multivalency needed to enhance UBQLN2 phase separation.Compact K11- and K48-linked Ub4 chains destabilized UBQLN2 phase separation, while extended M1- and K63-linked Ub4 promoted UBQLN2 phase separation.Chain conformation and accessibility of the Ub interacting surface is a driving factor of UBQLN2/polyUb co-phase separation.UBQLN2 condensates assemble during in vitro enzymatic assembly of K63-linked polyUb chains as free ubiquitin is depleted.

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“…Ubiquilin-2 (UBQLN2) is one of the four members of the ubiquilin (UBQLN) family in the human genome encoded by the U BQLN2 gene located on chromosome Xp11.21 (Kaye and Shows 2000 ). It is expressed in various tissues, but the highest expression levels are found in muscles and brain (Lin et al 2021 ). UBQLN2 localizes mainly in the cytoplasm where it functions in the maintenance of proteostasis.…”

Section: Autophagic Genes Involved In Alsmentioning

confidence: 99%

Autophagy Dysfunction in ALS: from Transport to Protein Degradation

Cozzi

Ferrari

2022

J Mol Neurosci

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons (MNs). Since the identification of the first ALS mutation in 1993, more than 40 genes have been associated with the disorder. The most frequent genetic causes of ALS are represented by mutated genes whose products challenge proteostasis, becoming unable to properly fold and consequently aggregating into inclusions that impose proteotoxic stress on affected cells. In this context, increasing evidence supports the central role played by autophagy dysfunctions in the pathogenesis of ALS. Indeed, in early stages of disease, high levels of proteins involved in autophagy are present in ALS MNs; but at the same time, with neurodegeneration progression, autophagy-mediated degradation decreases, often as a result of the accumulation of toxic protein aggregates in affected cells. Autophagy is a complex multistep pathway that has a central role in maintaining cellular homeostasis. Several proteins are involved in its tight regulation, and importantly a relevant fraction of ALS-related genes encodes products that directly take part in autophagy, further underlining the relevance of this key protein degradation system in disease onset and progression. In this review, we report the most relevant findings concerning ALS genes whose products are involved in the several steps of the autophagic pathway, from phagophore formation to autophagosome maturation and transport and finally to substrate degradation.

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UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD

Cited by 23 publications

References 190 publications

Mechanistic insights into enhancement or inhibition of phase separation by different polyubiquitin chains

Mechanistic insights into enhancement or inhibition of phase separation by different polyubiquitin chains

Mechanistic insights into the enhancement or inhibition of phase separation by polyubiquitin chains of different lengths or linkages

Autophagy Dysfunction in ALS: from Transport to Protein Degradation

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