RESUMO
The initiation and maintenance of adaptive immunity require multifaceted modes of communication between different types of immune cells, including direct intercellular contact, secreted soluble signaling molecules, and extracellular vesicles (EVs). EVs can be formed as microvesicles directly pinched off from the plasma membrane or as exosomes secreted by multivesicular endosomes. Membrane receptors guide EVs to specific target cells, allowing directional transfer of specific and complex signaling cues. EVs are released by most, if not all, immune cells. Depending on the type and status of their originating cell, EVs may facilitate the initiation, expansion, maintenance, or silencing of adaptive immune responses. This review focusses on EVs from professional antigen-presenting cells, their demonstrated and speculated roles, and their potential for cancer immunotherapy.
Assuntos
Apresentação de Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Vesículas Extracelulares/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Transporte Biológico , Micropartículas Derivadas de Células/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Epiteliais/metabolismo , Exossomos/metabolismo , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/imunologia , Humanos , Tolerância Imunológica , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
RNA quality control relies on co-factors and adaptors to identify and prepare substrates for degradation by ribonucleases such as the 3' to 5' ribonucleolytic RNA exosome. Here, we determined cryogenic electron microscopy structures of human nuclear exosome targeting (NEXT) complexes bound to RNA that reveal mechanistic insights to substrate recognition and early steps that precede RNA handover to the exosome. The structures illuminate ZCCHC8 as a scaffold, mediating homodimerization while embracing the MTR4 helicase and flexibly anchoring RBM7 to the helicase core. All three subunits collaborate to bind the RNA, with RBM7 and ZCCHC8 surveying sequences upstream of the 3' end to facilitate RNA capture by MTR4. ZCCHC8 obscures MTR4 surfaces important for RNA binding and extrusion as well as MPP6-dependent recruitment and docking onto the RNA exosome core, interactions that contribute to RNA surveillance by coordinating RNA capture, translocation, and extrusion from the helicase to the exosome for decay.
Assuntos
Exossomos , RNA Helicases DEAD-box/metabolismo , DNA Helicases/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Exossomos/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Ligação Proteica , RNA/metabolismo , Estabilidade de RNARESUMO
Exosomes are small, single-membrane, secreted organelles of â¼30 to â¼200 nm in diameter that have the same topology as the cell and are enriched in selected proteins, lipids, nucleic acids, and glycoconjugates. Exosomes contain an array of membrane-associated, high-order oligomeric protein complexes, display pronounced molecular heterogeneity, and are created by budding at both plasma and endosome membranes. Exosome biogenesis is a mechanism of protein quality control, and once released, exosomes have activities as diverse as remodeling the extracellular matrix and transmitting signals and molecules to other cells. This pathway of intercellular vesicle traffic plays important roles in many aspects of human health and disease, including development, immunity, tissue homeostasis, cancer, and neurodegenerative diseases. In addition, viruses co-opt exosome biogenesis pathways both for assembling infectious particles and for establishing host permissiveness. On the basis of these and other properties, exosomes are being developed as therapeutic agents in multiple disease models.
Assuntos
Exossomos/metabolismo , Animais , Transporte Biológico , Exossomos/imunologia , Exossomos/fisiologia , Exossomos/ultraestrutura , Matriz Extracelular/metabolismo , Humanos , Neoplasias , Doenças Neurodegenerativas , Multimerização Proteica , Transdução de SinaisRESUMO
There is growing interest surrounding the diagnostic and therapeutic potential of exosomes, but a definitive description of these extracellular vesicles remains elusive. In this issue, Jeppesen et al. characterize exosomes following a strict isolation protocol and in so doing challenge several of the accepted properties of these agents of intercellular communication.
Assuntos
Exossomos , Vesículas Extracelulares , Comunicação CelularRESUMO
The heterogeneity of small extracellular vesicles and presence of non-vesicular extracellular matter have led to debate about contents and functional properties of exosomes. Here, we employ high-resolution density gradient fractionation and direct immunoaffinity capture to precisely characterize the RNA, DNA, and protein constituents of exosomes and other non-vesicle material. Extracellular RNA, RNA-binding proteins, and other cellular proteins are differentially expressed in exosomes and non-vesicle compartments. Argonaute 1-4, glycolytic enzymes, and cytoskeletal proteins were not detected in exosomes. We identify annexin A1 as a specific marker for microvesicles that are shed directly from the plasma membrane. We further show that small extracellular vesicles are not vehicles of active DNA release. Instead, we propose a new model for active secretion of extracellular DNA through an autophagy- and multivesicular-endosome-dependent but exosome-independent mechanism. This study demonstrates the need for a reassessment of exosome composition and offers a framework for a clearer understanding of extracellular vesicle heterogeneity.
Assuntos
Exossomos/metabolismo , Exossomos/fisiologia , Anexina A1/metabolismo , Proteínas Argonautas/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Micropartículas Derivadas de Células/metabolismo , DNA/metabolismo , Exossomos/química , Vesículas Extracelulares , Feminino , Humanos , Lisossomos/metabolismo , Masculino , Proteínas/metabolismo , RNA/metabolismoRESUMO
The RNA exosome is a 3' to 5' ribonuclease that plays a fundamental role in maturation, quality control, and turnover of nearly all types of RNA produced in eukaryotic cells. Here, we present an overview of the structure, composition, and functions of the RNA exosome, including various cytoplasmic and nuclear exosome co-factors and associated protein complexes. To view this SnapShot, open or download the PDF.
Assuntos
Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Exossomos/metabolismo , RNA Mensageiro/metabolismo , RNA Ribossômico/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Humanos , RNA Helicases/metabolismo , Estabilidade de RNARESUMO
PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches.
Assuntos
Antígeno B7-H1/metabolismo , Antígeno B7-H1/fisiologia , Microambiente Tumoral/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Exossomos/metabolismo , Humanos , Imunoterapia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Microambiente Tumoral/fisiologiaRESUMO
Here, we describe a novel pathogenic entity, the activated PMN (polymorphonuclear leukocyte, i.e., neutrophil)-derived exosome. These CD63+/CD66b+ nanovesicles acquire surface-bound neutrophil elastase (NE) during PMN degranulation, NE being oriented in a configuration resistant to α1-antitrypsin (α1AT). These exosomes bind and degrade extracellular matrix (ECM) via the integrin Mac-1 and NE, respectively, causing the hallmarks of chronic obstructive pulmonary disease (COPD). Due to both ECM targeting and α1AT resistance, exosomal NE is far more potent than free NE. Importantly, such PMN-derived exosomes exist in clinical specimens from subjects with COPD but not healthy controls and are capable of transferring a COPD-like phenotype from humans to mice in an NE-driven manner. Similar findings were observed for another neutrophil-driven disease of ECM remodeling (bronchopulmonary dysplasia [BPD]). These findings reveal an unappreciated role for exosomes in the pathogenesis of disorders of ECM homeostasis such as COPD and BPD, providing a critical mechanism for proteolytic damage.
Assuntos
Exossomos/fisiologia , Neutrófilos/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/citologia , Células Cultivadas , Matriz Extracelular/metabolismo , Feminino , Humanos , Inflamação , Integrinas , Elastase de Leucócito/metabolismo , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , alfa 1-Antitripsina/metabolismoRESUMO
The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain, mediates various forms of synaptic plasticity, and has been implicated in neurodevelopmental disorders. However, little is known about Arc's molecular function and evolutionary origins. Here, we show that Arc self-assembles into virus-like capsids that encapsulate RNA. Endogenous Arc protein is released from neurons in extracellular vesicles that mediate the transfer of Arc mRNA into new target cells, where it can undergo activity-dependent translation. Purified Arc capsids are endocytosed and are able to transfer Arc mRNA into the cytoplasm of neurons. These results show that Arc exhibits similar molecular properties to retroviral Gag proteins. Evolutionary analysis indicates that Arc is derived from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestors to retroviruses. These findings suggest that Gag retroelements have been repurposed during evolution to mediate intercellular communication in the nervous system.
Assuntos
Proteínas do Citoesqueleto/metabolismo , Exossomos/metabolismo , Produtos do Gene gag/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Animais , Células Cultivadas , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/genética , Endocitose , Feminino , Produtos do Gene gag/química , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Neurônios/fisiologiaRESUMO
Cellular membranes can form two principally different involutions, which either exclude or contain cytosol. The 'classical' budding reactions, such as those occurring during endocytosis or formation of exocytic vesicles, involve proteins that assemble on the cytosol-excluding face of the bud neck. Inverse membrane involution occurs in a wide range of cellular processes, supporting cytokinesis, endosome maturation, autophagy, membrane repair and many other processes. Such inverse membrane remodelling is mediated by a heteromultimeric protein machinery known as endosomal sorting complex required for transport (ESCRT). ESCRT proteins assemble on the cytosolic (or nucleoplasmic) face of the neck of the forming involution and cooperate with the ATPase VPS4 to drive membrane scission or sealing. Here, we review similarities and differences of various ESCRT-dependent processes, with special emphasis on mechanisms of ESCRT recruitment.
Assuntos
Membrana Celular/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Neurônios/citologia , Membrana Nuclear/metabolismo , Replicação Viral/fisiologia , Animais , Citocinese , Endossomos/metabolismo , Exossomos/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Neurônios/metabolismo , Fagossomos/metabolismo , Transporte Proteico , Espastina/metabolismoRESUMO
Reciprocal interactions between tumor cells and their microenvironment drive cancer progression and therapy resistance. In this issue, Nabet et al. demonstrate that dynamic feedback between tumor and stroma subverts normal inflammatory responses by triggering the release of exosomes containing unshielded RNAs that activate pattern recognition receptors, thereby promoting tumor growth and metastasis.
Assuntos
Neoplasias/genética , RNA , Exossomos/genética , HumanosRESUMO
Interactions between stromal fibroblasts and cancer cells generate signals for cancer progression, therapy resistance, and inflammatory responses. Although endogenous RNAs acting as damage-associated molecular patterns (DAMPs) for pattern recognition receptors (PRRs) may represent one such signal, these RNAs must remain unrecognized under non-pathological conditions. We show that triggering of stromal NOTCH-MYC by breast cancer cells results in a POL3-driven increase in RN7SL1, an endogenous RNA normally shielded by RNA binding proteins SRP9/14. This increase in RN7SL1 alters its stoichiometry with SRP9/14 and generates unshielded RN7SL1 in stromal exosomes. After exosome transfer to immune cells, unshielded RN7SL1 drives an inflammatory response. Upon transfer to breast cancer cells, unshielded RN7SL1 activates the PRR RIG-I to enhance tumor growth, metastasis, and therapy resistance. Corroborated by evidence from patient tumors and blood, these results demonstrate that regulation of RNA unshielding couples stromal activation with deployment of RNA DAMPs that promote aggressive features of cancer. VIDEO ABSTRACT.
Assuntos
Neoplasias da Mama/patologia , Exossomos/patologia , RNA não Traduzido/metabolismo , Células Estromais/patologia , Microambiente Tumoral , Neoplasias da Mama/metabolismo , Proteína DEAD-box 58/metabolismo , Exossomos/metabolismo , Humanos , Fatores Reguladores de Interferon/metabolismo , Células MCF-7 , Metástase Neoplásica , RNA Polimerase III/genética , RNA Polimerase III/metabolismo , Receptores Imunológicos , Receptores de Reconhecimento de Padrão/metabolismo , Partícula de Reconhecimento de Sinal/metabolismo , Células Estromais/metabolismo , Viroses/metabolismoRESUMO
The liver plays a pivotal role in metabolism and xenobiotic detoxification, processes that must be particularly efficient when animals are active and feed. A major question is how the liver adapts to these diurnal changes in physiology. Here, we show that, in mice, liver mass, hepatocyte size, and protein levels follow a daily rhythm, whose amplitude depends on both feeding-fasting and light-dark cycles. Correlative evidence suggests that the daily oscillation in global protein accumulation depends on a similar fluctuation in ribosome number. Whereas rRNA genes are transcribed at similar rates throughout the day, some newly synthesized rRNAs are polyadenylated and degraded in the nucleus in a robustly diurnal fashion with a phase opposite to that of ribosomal protein synthesis. Based on studies with cultured fibroblasts, we propose that rRNAs not packaged into complete ribosomal subunits are polyadenylated by the poly(A) polymerase PAPD5 and degraded by the nuclear exosome.
Assuntos
Fígado/citologia , Fígado/fisiologia , Ribossomos/metabolismo , Animais , Núcleo Celular/metabolismo , Tamanho Celular , Ritmo Circadiano , Exossomos/metabolismo , Hepatócitos/citologia , Hepatócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fotoperíodo , Processamento Pós-Transcricional do RNA , RNA Ribossômico/genética , Proteínas Ribossômicas/genética , Ribossomos/químicaRESUMO
The nuclear RNA exosome is an essential multi-subunit complex that controls RNA homeostasis. Congenital mutations in RNA exosome genes are associated with neurodegenerative diseases. Little is known about the role of the RNA exosome in the cellular response to pathogens. Here, using NGS and human and mouse genetics, we show that influenza A virus (IAV) ribogenesis and growth are suppressed by impaired RNA exosome activity. Mechanistically, the nuclear RNA exosome coordinates the initial steps of viral transcription with RNAPII at host promoters. The viral polymerase complex co-opts the nuclear RNA exosome complex and cellular RNAs en route to 3' end degradation. Exosome deficiency uncouples chromatin targeting of the viral polymerase complex and the formation of cellular:viral RNA hybrids, which are essential RNA intermediates that license transcription of antisense genomic viral RNAs. Our results suggest that evolutionary arms races have shaped the cellular RNA quality control machinery.
Assuntos
Interações Hospedeiro-Patógeno , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Influenza Humana/virologia , RNA Polimerase II/metabolismo , Células A549 , Animais , Imunoprecipitação da Cromatina , Exorribonucleases/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Exossomos/metabolismo , Humanos , Espectrometria de Massas , Camundongos , Mutação , Doenças Neurodegenerativas/virologia , Proteínas de Ligação a RNA/genética , Ribossomos/genética , Transcrição GênicaRESUMO
Effective antiviral protection in multicellular organisms relies on both cell-autonomous and systemic immunity. Systemic immunity mediates the spread of antiviral signals from infection sites to distant uninfected tissues. In arthropods, RNA interference (RNAi) is responsible for antiviral defense. Here, we show that flies have a sophisticated systemic RNAi-based immunity mediated by macrophage-like haemocytes. Haemocytes take up dsRNA from infected cells and, through endogenous transposon reverse transcriptases, produce virus-derived complementary DNAs (vDNA). These vDNAs template de novo synthesis of secondary viral siRNAs (vsRNA), which are secreted in exosome-like vesicles. Strikingly, exosomes containing vsRNAs, purified from haemolymph of infected flies, confer passive protection against virus challenge in naive animals. Thus, similar to vertebrates, insects use immune cells to generate immunological memory in the form of stable vDNAs that generate systemic immunity, which is mediated by the vsRNA-containing exosomes.
Assuntos
Drosophila melanogaster/imunologia , Drosophila melanogaster/virologia , Hemócitos/imunologia , Sindbis virus/fisiologia , Imunidade Adaptativa , Animais , Proteínas Argonautas/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Exossomos/metabolismo , Hemócitos/efeitos dos fármacos , Hemócitos/virologia , Memória Imunológica , Interferência de RNA , RNA Viral/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Transcrição Reversa/efeitos dos fármacos , Sindbis virus/genética , Zidovudina/farmacologiaRESUMO
The MYCN oncoprotein binds active promoters in a heterodimer with its partner protein MAX. MYCN also interacts with the nuclear exosome, a 3'-5' exoribonuclease complex, suggesting a function in RNA metabolism. Here, we show that MYCN forms stable high-molecular-weight complexes with the exosome and multiple RNA-binding proteins. MYCN binds RNA in vitro and in cells via a conserved sequence termed MYCBoxI. In cells, MYCN associates with thousands of intronic transcripts together with the ZCCHC8 subunit of the nuclear exosome targeting complex and enhances their processing. Perturbing exosome function results in global re-localization of MYCN from promoters to intronic RNAs. On chromatin, MYCN is then replaced by the MNT(MXD6) repressor protein, inhibiting MYCN-dependent transcription. RNA-binding-deficient alleles show that RNA-binding limits MYCN's ability to activate cell growth-related genes but is required for MYCN's ability to promote progression through S phase and enhance the stress resilience of neuroblastoma cells.
Assuntos
Proteína Proto-Oncogênica N-Myc , Proteínas Nucleares , Proteínas Oncogênicas , Proteínas de Ligação a RNA , Proteína Proto-Oncogênica N-Myc/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Humanos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteínas Oncogênicas/metabolismo , Proteínas Oncogênicas/genética , Regiões Promotoras Genéticas , Linhagem Celular Tumoral , Neuroblastoma/metabolismo , Neuroblastoma/genética , Neuroblastoma/patologia , Exossomos/metabolismo , Exossomos/genética , Íntrons , Ligação Proteica , Núcleo Celular/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Regulação Neoplásica da Expressão Gênica , RNA/metabolismo , RNA/genética , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Proliferação de CélulasRESUMO
Dissecting the regulatory mechanisms controlling mammalian transcripts from production to degradation requires quantitative measurements of mRNA flow across the cell. We developed subcellular TimeLapse-seq to measure the rates at which RNAs are released from chromatin, exported from the nucleus, loaded onto polysomes, and degraded within the nucleus and cytoplasm in human and mouse cells. These rates varied substantially, yet transcripts from genes with related functions or targeted by the same transcription factors and RNA-binding proteins flowed across subcellular compartments with similar kinetics. Verifying these associations uncovered a link between DDX3X and nuclear export. For hundreds of RNA metabolism genes, most transcripts with retained introns were degraded by the nuclear exosome, while the remaining molecules were exported with stable cytoplasmic lifespans. Transcripts residing on chromatin for longer had extended poly(A) tails, whereas the reverse was observed for cytoplasmic mRNAs. Finally, machine learning identified molecular features that predicted the diverse life cycles of mRNAs.
Assuntos
Núcleo Celular , Cromatina , RNA Helicases DEAD-box , RNA Mensageiro , Animais , Humanos , Camundongos , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Núcleo Celular/metabolismo , Núcleo Celular/genética , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/genética , Cromatina/metabolismo , Cromatina/genética , Citoplasma/metabolismo , Citoplasma/genética , Estabilidade de RNA , Transporte Ativo do Núcleo Celular , Polirribossomos/metabolismo , Polirribossomos/genética , Aprendizado de Máquina , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Exossomos/metabolismo , Exossomos/genéticaRESUMO
Chromatin dynamics play an essential role in regulating DNA transaction processes, but it is unclear whether transcription-associated chromatin modifications control the mRNA ribonucleoparticles (mRNPs) pipeline from synthesis to nuclear exit. Here, we identify the yeast ISW1 chromatin remodeling complex as an unanticipated mRNP nuclear export surveillance factor that retains export-incompetent transcripts near their transcription site. This tethering activity of ISW1 requires chromatin binding and is independent of nucleosome sliding activity or changes in RNA polymerase II processivity. Combination of in vivo UV-crosslinking and genome-wide RNA immunoprecipitation assays show that Isw1 and its cofactors interact directly with premature mRNPs. Our results highlight that the concerted action of Isw1 and the nuclear exosome ensures accurate surveillance mechanism that proofreads the efficiency of mRNA biogenesis.
Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ribonucleoproteínas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Montagem e Desmontagem da Cromatina , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Exossomos/metabolismo , Complexos Multiproteicos/metabolismo , RNA Polimerase II/metabolismoRESUMO
We talk to authors Achim Keidel and Elena Conti about their paper "Concerted structural rearrangements enable RNA channeling into the cytoplasmic Ski238-Ski7-exosome assembly" (in this issue of Molecular Cell), staying focused on the scientific question while being open to new approaches and their preferred way to celebrate good news.
Assuntos
Exossomos , RNARESUMO
The Ski2-Ski3-Ski8 (Ski238) helicase complex directs cytoplasmic mRNAs toward the nucleolytic exosome complex for degradation. In yeast, the interaction between Ski238 and exosome requires the adaptor protein Ski7. We determined different cryo-EM structures of the Ski238 complex depicting the transition from a rigid autoinhibited closed conformation to a flexible active open conformation in which the Ski2 helicase module has detached from the rest of Ski238. The open conformation favors the interaction of the Ski3 subunit with exosome-bound Ski7, leading to the recruitment of the exosome. In the Ski238-Ski7-exosome holocomplex, the Ski2 helicase module binds the exosome cap, enabling the RNA to traverse from the helicase through the internal exosome channel to the Rrp44 exoribonuclease. Our study pinpoints how conformational changes within the Ski238 complex regulate exosome recruitment for RNA degradation. We also reveal the remarkable conservation of helicase-exosome RNA channeling mechanisms throughout eukaryotic nuclear and cytoplasmic exosome complexes.