RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control

Mohan, Harihar Milaganur; Trzeciakiewicz, Hanna; Pithadia, Amit S.; Crowley, Emily V; Pacitto, Regina; Safren, Nathaniel; Trotter, Bryce; Zhang, Chengxin; Zhou, Xiaogen; Zhang, Yang; Basrur, Venkatesha; Paulson, Henry L.; Sharkey, Lisa M.

doi:10.1007/s00018-022-04170-z

Cited by 3 publications

(3 citation statements)

References 78 publications

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“…A second possibility is that RTL8 incorporation disrupts proper localization of the PEG10 capsid or protein:protein interactions necessary for trafficking and release of VLPs. In support of this hypothesis, recent studies have shown RTL8 influencing the localization and function of UBQLN2 31 , and RTL8 could have a similar effect on PEG10. Detailed investigation of PEG10 capsid assembly and release is warranted to distinguish these possibilities.…”

Section: Discussionmentioning

confidence: 67%

“…UBQLN2 has also been reported to share a functional relationship with RTL8 , a domesticated retrotransposon that resembles PEG10 18,31 . Like PEG10 , RTL8 is a member of the Mart (or Mar) family of domesticated retrotransposons derived from the Ty3/ gypsy lineage 25 .…”

Section: Resultsmentioning

confidence: 99%

“…These failures are likely due, at least in part, to the existence of three highly similar and potentially redundant RTL8 genes, and due to their presence on the Xchromosome, which is excluded from typical GWAS studies. RTL8 interacts with UBQLN2 and contributes to protein quality control (PQC) 31 , and defects in PQC pathways are a hallmark of neurodegeneration [49][50][51] . In this context, RTL8 loss or mutation may mimic UBQLN2-mediated disease 52 , as loss-of-function mutations in RTL8 would result in elevated PEG10 VLP release.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The gag-like geneRTL8antagonizes PEG10-mediated virus like particles in humans

Campodonico-Burnett

Black

Lau

et al. 2023

Preprint

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Transposable elements can cause catastrophic genomic instability and are tightly regulated by the host through multiple restriction pathways. Domesticated elements are derived from these ancestors and have evolved adaptive roles but may retain pathological activity. For example, PEG10 is required for placentation but also promotes cancer and neurodegeneration. While much of PEG10 remains poorly understood, a unique feature is its ability to readily form virus-like particles (VLPs) which may contribute to its adaptive and pathological nature. However, comparable restriction networks that antagonize the harmful potential of domesticated genes like PEG10 remain unknown. Here, we describe restriction of PEG10 VLP abundance via UBQLN2 and the domesticated retrotransposon RTL8. The gag-like RTL8 antagonizes PEG10 through competitive incorporation into VLPs reminiscent of transposable element inhibitors from diverse eukaryotes. These results represent the first known instance of a retroelement-derived restriction factor antagonizing another domesticated retrotransposon and have implications for our understanding of PEG10 biology.

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Section: Discussionmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The gag-like geneRTL8antagonizes PEG10-mediated virus like particles in humans

Campodonico-Burnett

Black

Lau

et al. 2023

Preprint

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Targeting retrovirus-derivedRtl8aand8bcauses late onset obesity and neurodevelopmental defects

Fujioka

Shiura

Ishii

et al. 2023

Preprint

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Retrotransposon Gag-like (RTL) 8A, 8B and 8C are triplet genes of uncertain function that form a cluster on the X chromosome. They are eutherian-specific genes presumably derived from a certain retrovirus. Here, we demonstrate that Rtl8a and Rtl8b play an important role in growth and behavior via brain functions in the hypothalamus and prefrontal cortex. Rtl8a and Rtl8b double knockout (DKO) mice exhibited overgrowth due to hyperphagia from young adulthood and reduced social responses, increased apathy-like behavior. RTL8A and RTL8B proteins are localized to both the nucleus and cytoplasm of neurons presumably due to an N-terminal nuclear localization signal-like sequence. An increment in nucleus size was also detected in the neurons in the prefrontal cortex, suggesting neuronal dysfunction. These data give another strong evidence that retrovirus-derived acquired genes contributed to the establishment of the current eutherian developmental system in a wide variety of ways.

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Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate

Valentino,

Llivicota-Guaman,

Dao

et al. 2024

Preprint

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Ubiquitination is one of the most common post-translational modifications in eukaryotic cells. Depending on the architecture of polyubiquitin chains, substrate proteins can meet different cellular fates, but our understanding of how chain linkage controls protein fate remains limited. UBL-UBA shuttle proteins, such as UBQLN2, bind to ubiquitinated proteins and to the proteasome or other protein quality control machinery elements and play a role in substrate fate determination. Under physiological conditions, UBQLN2 forms biomolecular condensates through phase separation, a physicochemical phenomenon in which multivalent interactions drive the formation of a macromolecule-rich condensed phase. Ubiquitin and polyubiquitin chains modulate UBQLN2's phase separation in a linkage-dependent manner, suggesting a possible link to substrate fate determination, but polyubiquitinated substrates have not been examined directly. Herein, using sedimentation assays and microscopy, we show that polyubiquitinated substrates induce UBQLN2 phase separation and incorporate into the resulting condensates. This substrate effect is strongest with K63-linked substrates, intermediate with mixed-linkage substrates, and weakest with K48-linked substrates. Proteasomes can be recruited to these condensates, but proteasome activity towards K63-linked and mixed linkage substrates is inhibited in condensates. Substrates are also protected from deubiquitinases by UBQLN2-induced phase separation. Our results imply that phase separation can act as a regulatory switch that controls the fate of ubiquitinated substrates in a chain-linkage dependent manner, thus serving as an interpreter of the ubiquitin code.

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RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control

Cited by 3 publications

References 78 publications

The gag-like geneRTL8antagonizes PEG10-mediated virus like particles in humans

The gag-like geneRTL8antagonizes PEG10-mediated virus like particles in humans

Targeting retrovirus-derivedRtl8aand8bcauses late onset obesity and neurodevelopmental defects

Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate

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