Figure 1 - available via license: Creative Commons Attribution-NonCommercial 4.0 International
Content may be subject to copyright.
Possible role of Gemin5 in UsnRNP assembly. (A) Alignment of the Sm sites and neighboring nucleotides of the major spliceosomal U1, U2, U4, and U5 snRNAs. U4 snRNA, used in the present studies, is boxed. Sm site nucleotides are numbered 19 and colored blue to red in a 5 ′-to-3 ′ direction. Sm proteins F, E, G, D3, B, D1, and D2 are assembled on nucleotides 1-7 of the Sm sites to form Sm cores. (B,C ) Structures of the Gemin5 N-terminal tandem WD40 domains in complex with a 13-nucleotide (nt) (B) and a 7-nt (C ) oligomer containing a complete or partial Sm site, respectively (based on Jin et al. 2016). The two RNA molecules bind with different registers across a positively charged concave surface formed by both WD40 domains. Three consecutive uridines (U5, U6, and U7 or U3, U4, and U5 of the Sm site) bind in an analogous manner and at identical pockets to the center of the protein (black lines). Nucleotides 3 ′ of U7 in B lack extensive contacts to the protein. U8 in C occupies a pocket on the second WD40 domain that also accommodates the m 7 G cap (see D). (D) Binding of an m 7 GpppG mimic of a 5 ′-capped snRNA to a pocket on the second WD40 domain (based on Xu et al. 2016). The second guanine base is disordered in the structure. (Close-up) N2 of m 7 G is buried in the pocket. An m 2,2,7 G cap bearing two additional methyl groups on N2 could not be accommodated due to the disruption of hydrogen bonds and steric hindrance. (E) Model for the role of Gemin5 in Sm core assembly. Gemin5 could bind snRNAs concomitantly via the m 7 G cap and the Sm site. Nucleotides 3 ′ of a Sm site would be free to engage in initial contacts to the partially assembled Sm proteins on the SMN complex. A shift in the register of Sm site binding on Gemin5 could feed Sm site nucleotides 6 and 7 into their binding pockets on D1 and D2, respectively. The shift in register could involve a loop of the first WD40 domain occupying a position where Sm site nucleotides 1-3 are initially bound on Gemin5. After subsequent handover of Sm site nucleotides 1, 2, and 3 to Sm proteins F, E, and G, respectively, Gemin5 might still hold onto the cap, protecting it from hypermethylation until the D3-B heterodimer has been assembled on Sm site nucleotides 4 and 5. After assembly of the Sm core has been completed, another handover of the cap from Gemin5 to the cap methyltransferase TGS1 would have to occur in this scenario.
Source publication
Macromolecular complexes, rather than individual biopolymers, perform many cellular activities. Faithful assembly of these complexes in vivo is therefore a vital challenge of all cells, and its failure can have fatal consequences. To form functional complexes, cells use elaborate measures to select the “right” components and combine them into worki...
Citations
... As an SMN complex member, GEMIN5 serves as the pre-snRNA binding protein, fulfilling a critical role in successful snRNP biogenesis (Battle et al., 2006). This process appears to be dependent on the previously mentioned WD-40 repeat domains, which simultaneously interact with the m 7 G cap and Sm site of snRNA transcripts, ultimately allowing for the assembly of the Sm proteins around the Sm site by the SMN complex (Wahl and Fischer, 2016). Further, GEMIN5 is also able to provide a level of quality control in this process, as it recognizes and rejects defective or unassembled pre-snRNA transcripts, guiding them to P-bodies for degradation, an action which likely explains the localization of the protein within these bodies ( Review Jiang et al., 2018). ...
... (A) Cytoplasmic GEMIN5 binds with snRNA exported from the nucleus via the nucleoporin complex (NPC). This binding occurs at the Smith (Sm) site and m 7 G cap (Wahl and Fischer, 2016). (B) This binding between GEMIN5 and snRNA then allows for the binding of the toroidal Sm core, previously constructed by the PRMT5 complex, around the snRNA via the survival motor neuron (SMN) complex (Neuenkirchen et al., 2015). ...
The recent identification of a neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) has resulted in an increased interest in GEMIN5, a multifunction RNA-binding protein. As the largest member of the survival motor neuron complex, GEMIN5 plays a key role in the biogenesis of small nuclear ribonucleoproteins while also exhibiting translational regulatory functions as an independent protein. Although many questions remain regarding both the pathogenesis and pathophysiology of this new disorder, considerable progress has been made in the brief time since its discovery. In this review, we examine GEMIN5 within the context of NEDCAM, focusing on the structure, function, and expression of the protein specifically in regard to the disorder itself. Additionally, we explore the current animal models of NEDCAM, as well as potential molecular pathways for treatment and future directions of study. This review provides a comprehensive overview of recent advances in our understanding of this unique member of the survival motor neuron complex.
... The copyright holder for this preprint this version posted August 20, 2023. ; https://doi.org/10.1101/2023.08.19.553944 doi: bioRxiv preprint A1 in U7 snRNA flank the key nucleotides in the Sm site known to bind Gemin5 (24,(86)(87)(88)(89). The lack of this competition could therefore allow Gemin5 to find its binding site in Drosophila U7 snRNA. ...
... Binding of Gemin5 to U7 snRNA. The recognition of the spliceosomal AAUUUUGG consensus sequence by Gemin5 (24)(25)(26) critically depends on the second adenosine, and the first and third uridines (24,(86)(87)(88)(89). Surprisingly, despite containing the same nucleotides in these positions, U7 snRNA does not interact with Gemin5 both in vivo (24) and in vitro (this study). ...
U7 snRNA is a 60-nucleotide component of U7 snRNP, a multi-subunit endonuclease that cleaves precursors of metazoan replication-dependent histone mRNAs at the 3’ end, hence generating mature histone mRNAs. The Sm site in U7 snRNA differs from the Sm site in spliceosomal snRNAs and promotes the assembly of a unique Sm ring containing Lsm10 and Lsm11 instead of SmD1 and SmD2 found in the spliceosomal snRNPs. The assembly of the spliceosomal Sm ring depends on the SMN complex, with one of its nine subunits, Gemin5, recognizing the spliceosomal Sm site. While the assembly of the U7-specific Sm ring also requires the SMN complex, the unusual Sm site of U7 snRNA is not recognized by Gemin5, and the identity of its counterpart that performs this function in biogenesis of U7 snRNP, has not been determined. Here, we looked for proteins that bind U7 snRNA but not to its mutant altered within the Sm site. We identified Polypyrimidine Tract-Binding Protein 1 (PTBP1) as the main protein that meets this specificity. Binding of PTBP1 to U7 snRNA also depends on the upstream CUCUUU motif that base pairs with histone pre-mRNAs and defines substrate specificity of U7 snRNP. Thus, PTBP1 simultaneously recognizes two functionally essential and highly conserved sites within U7 snRNA. In addition to PTBP1, U7 snRNA interacts with hnRNP A1, which recognizes a different part of the U7-specific Sm site. Interestingly, the two proteins can form with U7 snRNA a larger complex, which also contains SMN protein, a subunit of the SMN complex. Altogether, these results raise the possibility that PTBP1 and hnRNP A1 act collectively to substitute for Gemin5 in the assembly of U7-specific Sm ring.
... The SMN protein is at the center of the complex and acts by directly binding PRMT5methylated residues (Friesen et al. 2001a;Selenko et al. 2001;Cote and Richard 2005;Tripsianes et al. 2011), hence bringing multiple components of the SMN complex to the vicinity of the Sm proteins. Among these components, Gemin5 recognizes spliceosomal snRNAs as correct assembly targets by simultaneously binding to their monomethylated cap structure and Sm site (Battle et al. 2006b;Lau et al. 2009;Yong et al. 2010;Wahl and eukaryotic mRNAs (Mandel et al. 2008;Liu and Moore 2021). While Lsm10 is relatively small, resembling in size most Sm proteins (Pillai et al. 2001), Lsm11 has an extended Nterminal region of about 150 amino acids that is essential for the activity of U7 snRNP in 3' end processing (Pillai et al. 2003;Sun et al. 2020). ...
U7 snRNP is a multi-subunit endonuclease required for 3’ end processing of metazoan replication-dependent histone pre-mRNAs. In contrast to the spliceosomal snRNPs, U7 snRNP lacks the Sm subunits D1 and D2 and instead contains two related proteins, Lsm10 and Lsm11. The remaining five subunits of the U7 heptameric Sm ring, SmE, F, G, B and D3, are shared with the spliceosomal snRNPs. The pathway that assembles the unique ring of U7 snRNP is unknown. Here, we show that a heterodimer of Lsm10 and Lsm11 tightly interacts with the methylosome, a complex of the arginine methyltransferase PRMT5, MEP50 and pICln known to methylate arginines in the C-terminal regions of the Sm proteins B, D1 and D3 during the spliceosomal Sm ring assembly. Both biochemical and Cryo-EM structural studies demonstrate that the interaction is mediated by PRMT5, which binds and methylates two arginine residues in the N-terminal region of Lsm11. Surprisingly, PRMT5 also methylates an N-terminal arginine in SmE, a subunit that does not undergo this type of modification during the biogenesis of the spliceosomal snRNPs. An intriguing possibility is that the unique methylation pattern of Lsm11 and SmE plays a vital role in the assembly of the U7 snRNP.
... The SMN protein is at the center of the complex and acts by directly binding PRMT5methylated residues (Friesen et al. 2001a;Selenko et al. 2001;Cote and Richard 2005;Tripsianes et al. 2011), hence bringing multiple components of the SMN complex to the vicinity of the Sm proteins. Among these components, Gemin5 recognizes spliceosomal snRNAs as correct assembly targets by simultaneously binding to their monomethylated cap structure and Sm site (Battle et al. 2006b;Lau et al. 2009;Yong et al. 2010;Wahl and eukaryotic mRNAs (Mandel et al. 2008;Liu and Moore 2021). While Lsm10 is relatively small, resembling in size most Sm proteins (Pillai et al. 2001), Lsm11 has an extended Nterminal region of about 150 amino acids that is essential for the activity of U7 snRNP in 3' end processing (Pillai et al. 2003;Sun et al. 2020). ...
U7 snRNP is a multi-subunit endonuclease required for 3′ end processing of metazoan replication-dependent histone pre-mRNAs. In contrast to the spliceosomal snRNPs, U7 snRNP lacks the Sm subunits D1 and D2 and instead contains two related proteins, Lsm10 and Lsm11. The remaining five subunits of the U7 heptameric Sm ring, SmE, F, G, B and D3, are shared with the spliceosomal snRNPs. The pathway that assembles the unique ring of U7 snRNP is unknown. Here, we show that a heterodimer of Lsm10 and Lsm11 tightly interacts with the methylosome, a complex of the arginine methyltransferase PRMT5, MEP50 and pICln known to methylate arginines in the C-terminal regions of the Sm proteins B, D1 and D3 during the spliceosomal Sm ring assembly. Both biochemical and Cryo-EM structural studies demonstrate that the interaction is mediated by PRMT5, which binds and methylates two arginine residues in the N-terminal region of Lsm11. Surprisingly, PRMT5 also methylates an N-terminal arginine in SmE, a subunit that does not undergo this type of modification during the biogenesis of the spliceosomal snRNPs. An intriguing possibility is that the unique methylation pattern of Lsm11 and SmE plays a vital role in the assembly of the U7 snRNP.
... In vertebrates this macromolecular machinery consists of nine factors, including the survival motor neuron (SMN) protein, Gemins2-8 (abbreviated G2-8 with prefix Hs for human and Sp for Schizosaccharomyces pombe throughout the paper) and unrip (27)(28)(29)(30)(31)(32)(33). While SMN and G2 engage with the Sm proteins and aid in the release of pI-Cln, G5 has been reported to be the snRNA recruiter during UsnRNP assembly (29,(34)(35)(36)(37). ...
The macromolecular SMN complex facilitates the formation of Sm-class ribonucleoproteins involved in mRNA processing (UsnRNPs). While biochemical studies have revealed key activities of the SMN complex, its structural investigation is lagging behind. Here we report on the identification and structural determination of the SMN complex from the lower eukaryote Schizosaccharomyces pombe, consisting of SMN, Gemin2, 6, 7, 8 and Sm proteins. The core of the SMN complex is formed by several copies of SMN tethered through its C-terminal alpha-helices arranged with alternating polarity. This creates a central platform onto which Gemin8 binds and recruits Gemins 6 and 7. The N-terminal parts of the SMN molecules extrude via flexible linkers from the core and enable binding of Gemin2 and Sm proteins. Our data identify the SMN complex as a multivalent hub where Sm proteins are collected in its periphery to allow their joining with UsnRNA.
... Gemin4 usually forms a complex with Gemin3, but its role is unknown (28). Gemin5 is the component to initially bind pre-snRNAs and deliver them to the rest of the SMN complex for assembly into the Sm core (29), and is currently considered to be the protein conferring the RNA assembly specificity by direct recognition of the snRNP code (30)(31)(32)(33)(34)(35). ...
... This is the central question of chaperone-mediated Sm core assembly because Sm cores can form in vitro spontaneously and specifically on RNAs containing just the nonameric Sm site and it is the SMN complex that enhances the specificity of Sm core assembly (8,9). Although current knowledge considers that Gemin5 is the right protein by direct binding to the snRNP code and this model is partially supported by some experimental data (30)(31)(32)(33)(34)(35), there are several conflicting observations indicating that the problem is not solved yet. First, Sm core assembly is a highly conserved pathway in all eukaryotes, but there is no homolog of Gemin5 in many lower eukaryotes (16,35). ...
... Although current knowledge considers that Gemin5 is the right protein by direct binding to the snRNP code and this model is partially supported by some experimental data (30)(31)(32)(33)(34)(35), there are several conflicting observations indicating that the problem is not solved yet. First, Sm core assembly is a highly conserved pathway in all eukaryotes, but there is no homolog of Gemin5 in many lower eukaryotes (16,35). Second, recent structural and biochemical studies showed that the RNAbinding specificity of Gemin5 is only able to recognize part of the Sm site, AUUU, not to mention the full feature of the snRNP code (32)(33)(34). ...
The assembly of snRNP cores, in which seven Sm proteins, D1/D2/F/E/G/D3/B, form a ring around the nonameric Sm site of snRNAs, is the early step of spliceosome formation and essential to eukaryotes. It is mediated by the PMRT5 and SMN complexes sequentially in vivo. SMN deficiency causes neurodegenerative disease spinal muscular atrophy (SMA). How the SMN complex assembles snRNP cores is largely unknown, especially how the SMN complex achieves high RNA assembly specificity and how it is released. Here we show, using crystallographic and biochemical approaches, that Gemin2 of the SMN complex enhances RNA specificity of SmD1/D2/F/E/G via a negative cooperativity between Gemin2 and RNA in binding SmD1/D2/F/E/G. Gemin2, independent of its N-tail, constrains the horseshoe-shaped SmD1/D2/F/E/G from outside in a physiologically relevant, narrow state, enabling high RNA specificity. Moreover, the assembly of RNAs inside widens SmD1/D2/F/E/G, causes the release of Gemin2/SMN allosterically and allows SmD3/B to join. The assembly of SmD3/B further facilitates the release of Gemin2/SMN. This is the first to show negative cooperativity in snRNP assembly, which provides insights into RNA selection and the SMN complex's release. These findings reveal a basic mechanism of snRNP core assembly and facilitate pathogenesis studies of SMA.
... Gemin5 is the component to initially bind precursor (pre)-snRNAs and deliver them to the rest of the SMN complex for assembly into the Sm core [35]. Although it had long been considered as the protein conferring the RNA assembly specificity by direct recognition of the snRNP code [36][37][38][39][40][41], our recent study indicates that it is Gemin2 that plays the role of enhancing RNA assembly specificity by an unusual way, via a negative cooperativity with RNA in binding to 5Sm (https://doi.org/10.1101/312124). ...
... The final structure has improved quality as indicated by the reduction of R and Rfree from 25.3% and 33.2% to 21.7% and 29.5% respectively (Supplementary Table S1). The final model (PDB code 5XJL) contains SmD1 (residues 1-81), SmD2 (residues 21-77 and 89-117), SmF (residues 3-76), SmE (residues 14-90), SmG (residues 8-52 and 55-72), Gemin2 (residues 22-31, 48-73, 79-124, 135-151, and 174-278), and SMN (residues [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]. Ramachandran plot shows 95.8% of the dihedral angles in favored region, 2.6% in additional allowed region, and 1.6 (9 out of 576) in disallowed region (Supplementary Table S1). ...
Sm-class ribonucleoprotein particles (RNPs) are ring-shaped structures (Sm cores) formed by Sm hetero-heptamer around a segment of RNA, containing a nonameric oligoribonucleotide, PuAUUUNUGPu, followed by a stem-loop, and are basic structural modules critical for stability and functions of spliceosomal, telemorase and U7 RNPs. In Sm-class RNP assembly, assembly factor Gemin2 not only binds SmD1/D2/F/E/G (5Sm), but also serves as a checkpoint via a negative cooperativity mechanism: Gemin2 constricts the horseshoe-shaped 5Sm in a narrow conformation from outside, preventing non-cognate RNA and SmD3/B from joining; only cognate RNA can bind inside 5Sm and widen 5Sm, dissociating Gemin2 from 5Sm and recruiting SmD3/B. However, the structural mechanics is unknown. Here I describe a coordinate-improved structure of 5Sm bound by Gemin2/SMN. Moreover, via new analysis, comparison of this structure with those of newly coordinate-improved mature U1 and U4 Sm cores reveals how RNAs are selected, 5Sm conformation is changed, and Gemin2 is dissociated from 5Sm. Based on structure-guided sequence alignments, this assembly model is proposed to be conserved for all Sm cores in all eukaryotes. Finally, evolution of the assembly machinery is proposed and implications in spinal muscular atrophy are discussed.
... Sm core assembly is a pivotal step of snRNP biogenesis and essential for eukaryotes [4]. Early studies established that Sm core assembly can occur spontaneously in vitro by mixing the three Sm hetero-oligomers, SmD1/D2, SmF/E/G and SmD3/B, with snRNA, or even oligoribonucleotide 5 considered to be the protein conferring the RNA assembly specificity by direct recognition of the snRNP code [27][28][29][30][31][32]. ...
... This is the central question of Sm core assembly because it is the reason why these chaperons have evolved and exist. Although current knowledge considers that Gemin5 is the right protein by direct binding to the snRNP code and this model is partially supported by some experimental data [27][28][29][30][31][32], there are several paradoxical observations this model cannot explain. First, Sm core assembly is a highly conserved pathway in all eukaryotes, but there is no homolog of Gemin5 in many lower eukaryotes [15,32]. ...
... Although current knowledge considers that Gemin5 is the right protein by direct binding to the snRNP code and this model is partially supported by some experimental data [27][28][29][30][31][32], there are several paradoxical observations this model cannot explain. First, Sm core assembly is a highly conserved pathway in all eukaryotes, but there is no homolog of Gemin5 in many lower eukaryotes [15,32]. Second, recent structural and biochemical studies showed that the RNA-binding specificity of Gemin5 is only able to recognize part of the Sm site, AUUU, not to mention the full feature of the snRNP code [29][30][31]. ...
The assembly of snRNP cores, in which seven Sm proteins, D1/D2/F/E/G/D3/B, form a ring around snRNAs, is the early step of spliceosome formation and essential to eukaryotes. It is mediated by the PMRT5 and SMN complexes sequentially in vivo. The deficiency of SMN causes neurodegenerative disease spinal muscular atrophy (SMA). How the SMN complex assembles snRNP cores in the second phase is largely unknown, especially how the SMN complex achieves stringent RNA specificity, ensuring seven Sm proteins assemble only around snRNAs, by requiring an extra 3'-adjacent stem-loop (SL) in addition to a nonameric Sm site RNA (PuAUUUNUGPu) on which snRNP cores can spontaneously form without chaperons in vitro. Moreover, how the SMN complex is released from snRNP cores is unknown. Here we show that Gemin2 of the SMN complex and RNA allosterically and mutually inhibit each other's binding to SmD1/D2/F/E/G, coupling RNA selection with the SMN complex's release. Using crystallographic and biochemical approaches, we found that Gemin2 constrains the horseshoe-shaped SmD1/D2/F/E/G in a physiologically relevant, narrow state, which prefers the snRNP-code (both the Sm site and 3'-SL)-containing RNA for assembly. Moreover, the assembly of RNA widens SmD1/D2/F/E/G, causes Gemin2's release allosterically and allows SmD3/B to join. By structural analysis we further propose a structural mechanism for the allosteric conformational changes. These findings provide deeper insights into the SMN complex's mode of action and snRNP assembly, and facilitate potential therapeutic studies of SMA.
... Gemin5 mediates recruitment of UsnRNAs onto the SMN complex. Recent structural data have elucidated an atomic model of how Gemin5 contacts the m 7 G-Cap and the Sm site of UsnRNAs (Jin et al. 2016;Wahl and Fischer 2016;Xu et al. 2016). This data allows educated guesses on the functional impact of specific posttranslational modifications. ...
Macromolecular complexes composed of proteins or proteins and nucleic acids rather than individual macromolecules mediate many cellular activities. Maintenance of these activities is essential for cell viability and requires the coordinated production of the individual complex components as well as their faithful incorporation into functional entities. Failure of complex assembly may have fatal consequences and can cause severe diseases. While many macromolecular complexes can form spontaneously in vitro, they often require aid from assembly factors including assembly chaperones in the crowded cellular environment. The assembly of RNA protein complexes implicated in the maturation of pre-mRNAs (termed UsnRNPs) has proven to be a paradigm to understand the action of assembly factors and chaperones. UsnRNPs are assembled by factors united in protein arginine methyltransferase 5 (PRMT5)- and survival motor neuron (SMN)-complexes, which act sequentially in the UsnRNP production line. While the PRMT5-complex pre-arranges specific sets of proteins into stable intermediates, the SMN complex displaces assembly factors from these intermediates and unites them with UsnRNA to form the assembled RNP. Despite advanced mechanistic understanding of UsnRNP assembly, our knowledge of regulatory features of this essential and ubiquitous cellular function remains remarkably incomplete. One may argue that the process operates as a default biosynthesis pathway and does not require sophisticated regulatory cues. Simple theoretical considerations and a number of experimental data, however, indicate that regulation of UsnRNP assembly most likely happens at multiple levels. This review will not only summarize how individual components of this assembly line act mechanistically but also why, how, and when the UsnRNP workflow might be regulated by means of posttranslational modification in response to cellular signaling cues.
... The SMN complex comprises the eponymous protein SMN, along with eight other proteins termed Gemins 2-8 and Unrip (Fischer et al., 1997;Hannus et al., 2000;Paushkin et al., 2000;Meister et al., 2001a;Gubitz et al., 2002;Pellizzoni et al., 2002a;Otter et al., 2007;Kroiss et al., 2008;Borg et al., 2015). Although SMN, Gemin2, and probably other components of the SMN complex engage with the Sm proteins and aid in the release of pICln (Grimm et al., 2013), Gemin5 has been reported to be the snRNA recruiter during UsnRNP assembly (Lau et al., 2009;Yong et al., 2010;Wahl and Fischer, 2016). All Sm-class UsnRNPs studied so far, including the U7snRNP particle containing a Sm/LSm hybrid core, require the SMN/PRMT5 system for assembly in vivo (Pillai et al., 2003). ...
... The active role of SMN and PRMT5 complexes in UsnRNP assembly has been proven and confirmed by many laboratories (Fischer et al., 1997;Meister et al., 2001a;Meister and Fischer, 2002;Paushkin et al., 2002;Pellizzoni et al., 2002b;Shpargel and Matera, 2005;Gonsalvez et al., 2007;Chari et al., 2008;Zhang et al., 2011;Neuenkirchen et al., 2015). For the late assembly factors (i.e., the SMN complex and its subunit Gemin5 in particular), a proofreading activity has been described (Pellizzoni et al., 2002b;Kroiss et al., 2008;Wahl and Fischer, 2016). This activity ensures the discrimination of nontarget RNAs during UsnRNP assembly, providing a plausible explanation for the requirement of the SMN complex for assembly. ...
Specialized assembly factors facilitate the formation of many macromolecular complexes in vivo. The formation of Sm core structures of spliceosomal U-rich small nuclear ribonucleoprotein particles (UsnRNPs) requires assembly factors united in protein arginine methyltransferase 5 (PRMT5) and survival motor neuron (SMN) complexes. We demonstrate that perturbations of this assembly machinery trigger complex cellular responses that prevent aggregation of unassembled Sm proteins. Inactivation of the SMN complex results in the initial tailback of Sm proteins on the PRMT5 complex, followed by down-regulation of their encoding mRNAs. In contrast, reduction of pICln, a PRMT5 complex subunit, leads to the retention of newly synthesized Sm proteins on ribosomes and their subsequent lysosomal degradation. Overexpression of Sm proteins under these conditions results in a surplus of Sm proteins over pICln, promoting their aggregation. Our studies identify an elaborate safeguarding system that prevents individual Sm proteins from aggregating, contributing to cellular UsnRNP homeostasis.
