A male germ-cell-specific ribosome controls male fertility

Li, Huiling; Huo, Yangao; He, Xi; Yao, Liping; Zhang, Hao; Cui, Yiqiang; Xiao, Huijuan; Xie, Wenxiu; Zhang, Dejiu; Wang, Yue; Zhang, Shu; Tu, Haixia; Cheng, Yiwei; Guo, Yueshuai; Cao, Xintao; Zhu, Yunfei; Jiang, Tao; Guo, Xuejiang; Qin, Yan; Sha, Jiahao

doi:10.1038/s41586-022-05508-0

Cited by 29 publications

(61 citation statements)

References 79 publications

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“…1C). Notably, a few ribosomal protein isoforms (e.g., RPL3L, RPL26L1, and RPL27L) and translation factors (e.g., EIF3 complex) showed differential enrichment, indicating functional heterogeneity in line with recent studies (29)(30)(31).…”

Section: Arc-ms Identifies Proteins Recruited To Translationally Acti...supporting

confidence: 84%

mRNA translational specialization by RBPMS presets the competence for cardiac commitment in hESCs

et al. 2023

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The blueprints of developing organs are preset at the early stages of embryogenesis. Transcriptional and epigenetic mechanisms are proposed to preset developmental trajectories. However, we reveal that the competence for the future cardiac fate of human embryonic stem cells (hESCs) is preset in pluripotency by a specialized mRNA translation circuit controlled by RBPMS. RBPMS is recruited to active ribosomes in hESCs to control the translation of essential factors needed for cardiac commitment program, including Wingless/Integrated (WNT) signaling. Consequently, RBPMS loss specifically and severely impedes cardiac mesoderm specification, leading to patterning and morphogenetic defects in human cardiac organoids. Mechanistically, RBPMS specializes mRNA translation, selectively via 3′UTR binding and globally by promoting translation initiation. Accordingly, RBPMS loss causes translation initiation defects highlighted by aberrant retention of the EIF3 complex and depletion of EIF5A from mRNAs, thereby abrogating ribosome recruitment. We demonstrate how future fate trajectories are programmed during embryogenesis by specialized mRNA translation.

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Section: Arc-ms Identifies Proteins Recruited To Translationally Acti...supporting

confidence: 84%

mRNA translational specialization by RBPMS presets the competence for cardiac commitment in hESCs

et al. 2023

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“…We show that this non-coding transcript is widely expressed in cancer/melanoma cells, but not in normal cells, to promote an immune-tolerant translatome. While evidence of specific ribosomal proteins contributing to ribosome heterogeneity continue to emerge [37], our data provide evidence that tailor-made ribosomes can be obtained also by incorporating individual lncRNAs into the ribosome. The incorporation of LISR into polysomes during the ISR generates cancer-specific ribosome and contribute to the emergence of DTPCs.…”

Section: Discussionmentioning

confidence: 78%

The cancer-specific lncRNALISRcustomizes ribosomes to suppress anti-tumour immunity

Cinque

Verheyden

Katopodi

et al. 2023

Preprint

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Responses to anticancer therapies in patients with advanced metastatic disease are often lower than 50% and the majority of patients initially responding develop resistance later on. Therapy resistance often follows an adaptation phase in which cancer cells exit the cell cycle and engage the Integrated Stress Response (ISR). Activation of this pathway induces the emergence of drug-tolerant persister cells via the block of CAP-dependent translation while enhancing translation of select mRNAs that support survival, migration and dampen immunogenicity. Little is known about the molecular mechanisms underlying ISR-dependent immune escape. Searching for transcripts specifically associated with polysomes upon ISR activation we identified the lncRNA LISR. We showed that this untranslated transcript, could suppress the production of putative neoantigens, while promoting translation of PD-L1 and other mRNAs involved in the formation of the glycocalyx. Accordingly, LISR locus is amplified in 60% of melanomas and its expression is increased in patients refractory to Immune Checkpoint Blockade (ICB). Consequently, inhibition of LISR stimulated anti-tumour immune responses both in vitro and in humanized and ICB-resistant patient-derived xenografts. This study establishes a link between lncRNAs, translation rewiring in cancer and immunogenicity, and identifies an RNA-based cancer-specific therapeutic strategy to overcome intrinsic resistance to ICB.

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“…The perturbed expression of pluripotency markers in RPL39L KO cells prompted us to further investigate their ability to differentiate. Given the relevance of RPL39L for the spermatogenic lineage 4,11 , we first subjected WT and RPL39L KO E14 lines to in vitro differentiation along this lineage using a previously described protocol 12 . The emergence of spermatocyte-like cells in the WT E14 mESC culture demonstrated that the protocol works as expected (Fig.…”

Section: Rpl39l Ko Mescs Exhibit Differentiation Defectsmentioning

confidence: 99%

“…Among these, autosomal-chromosome-encoded paralogs of X chromosome-linked RPs have strong expression bias for the male germ cell lineage, where they have been linked to highly specialized functions: RPL10L takes over the function of RPL10 upon X chromosome inactivation in the meiotic phase of spermatogenesis 3 , and RPL39L was implicated in the translation of long-lived, sperm cell-specific proteins 4 . However, the RPL39L mRNA was also observed in other cell types, including ovarian 5 and breast cancers 2 , as well as in lung cancer 6 and neuroblastoma 4 cell lines. Gene amplifications 7 and the hypomethylation of a specific CpG island 6 were proposed as mechanisms underlying RPL39L expression in cancers.…”

Section: Introductionmentioning

confidence: 99%

“…RPL39L differs from RPL39 by only 4 or 3 amino acids in human and mouse, respectively, explaining why antibodies that can distinguish RPL39L from RPL39 are still lacking. In addition, the high arginine/lysine content of RPL39L leads to the almost complete digestion of the protein during standard sample preparation for mass spectrometry, probably restricting its detection to cell types with very high expression 4 . As pure populations of RPL39L-containing ribosomes have not been obtained so far 4 , how RPL39/RPL39L ribosomes differ has also remained unclear.…”

Section: Introductionmentioning

confidence: 99%

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Ribosomal protein RPL39L is an efficiency factor in the cotranslational folding of proteins with alpha helical domains

Banerjee

Ataman

Smialek

et al. 2023

Preprint

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Increasingly many studies reveal how ribosome composition can be tuned to optimally translate the transcriptome of individual cell types. In this study, we investigated the expression pattern, structure within the ribosome and effect on protein synthesis of the ribosomal protein paralog 39L (RPL39L). With a novel mass spectrometric approach we have quantified the expression of RPL39L in human pluripotent cells, cancer cell lines and tissue samples, and in mouse germ cells. We generated RPL39L knock-out mouse embryonic stem cell (mESC) lines and demonstrated that RPL39L impacts the dynamics of translation, to support the pluripotency and differentiation, spontaneous and along the germ cell lineage. Most differences in protein abundance between WT and RPL39L KO lines were explained by widespread proteasomal activity. By CryoEM analysis of purified RPL39 and RPL39L-containing ribosomes we found that, unlike RPL39, RPL39L has two distinct conformations in the exposed segment of the nascent peptide exit tunnel, creating a distinct hydrophobic patch that has been predicted to support the efficient co-translational folding of alpha helices. Our study shows that ribosomal protein paralogs provide switchable modular components that can tune translation to the protein production needs of individual cell types.

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A male germ-cell-specific ribosome controls male fertility

Cited by 29 publications

References 79 publications

mRNA translational specialization by RBPMS presets the competence for cardiac commitment in hESCs

mRNA translational specialization by RBPMS presets the competence for cardiac commitment in hESCs

The cancer-specific lncRNALISRcustomizes ribosomes to suppress anti-tumour immunity

Ribosomal protein RPL39L is an efficiency factor in the cotranslational folding of proteins with alpha helical domains

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