The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex.

Ribosome biogenesis is a tightly controlled pathway that requires an intricate spatial and temporal interplay of protein networks. Most structural rRNA components are generated in the nucleolus and assembled into pre-ribosomal particles, which are transferred for further maturation to the nucleoplasm and cytoplasm. In metazoa, few regulatory components for these processes have been characterized. Previous work revealed a critical role for the SUMO-specific protease SENP3 in the nucleolar steps of ribosome biogenesis. We biochemically purified a SENP3-associated complex comprising PELP1, TEX10 and WDR18, and demonstrate that this complex is involved in maturation and nucleolar release of the large ribosomal subunit. We identified PELP1 and the PELP1-associated factor LAS1L as SENP3-sensitive targets of SUMO, and provide evidence that balanced SUMO conjugation/deconjugation determines the nucleolar partitioning of this complex. This defines the PELP1-TEX10-WDR18 complex as a regulator of ribosome biogenesis and suggests that its SUMO-controlled distribution coordinates the rate of ribosome formation. These findings contribute to the basic understanding of mammalian ribosome biogenesis and shed new light on the role of SUMO in this process.

SUMO routes ribosome maturation.

The control of ribosome biogenesis is a critical cellular nodal point, which ensures that protein synthesis is coordinated with cell growth and proliferation. Prior to their cytoplasmic assembly the 40S and 60S ribosomal subunits pass through the nucleolus and the nucleoplasm via a maturation pathway that involves a set of non-coding RNAs and non-ribosomal regulatory trans-acting factors. In mammalian cells the inventory of the required protein components is still fragmentary and it is largely unclear what drives the subcellular transitions and the exchange of protein components along the maturation pathway. However, recent data indicate that the dynamic post-translational modification by the ubiquitin-like SUMO modifier is critically involved in these processes. In particular, removal of SUMO from trans-acting factors by the SUMO-specific isopeptidase SENP3 is instrumental in the 60S maturation pathway in mammals. In an attempt to pinpoint the relevant targets of SENP3 we identified a novel SENP3-associated protein complex comprised of PELP1, TEX10 and WDR18. We demonstrated that this complex is involved in the nucleolar steps of 28S rRNA maturation and the subsequent nucleoplasmic transit of the 60S ribosomal subunit. Importantly, we found that PELP1 is a SENP3-sensitive target of SUMO and observed that lack of SENP3-mediated desumoylation prevents the nucleolar partitioning of the PELP1-TEX10-WDR18 complex. SUMO-dependent subnuclear trafficking may thus assist in coordinating the rate of ribosome formation. Here we propose that sumoylation of PELP1 serves as a quality control mechanism that restricts pre-mature loading of the PELP1-WDR18-TEX10 complex to 60S particles thereby limiting ribosome maturation. We further hypothesize that the PELP1-associated AAA-ATPase MDN1 may be part of this surveillance pathway.

SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans.

Correlative evidence links stress, accumulation of oxidative cellular damage, and aging in several species. Genetic studies in species ranging from yeast to mammals revealed several pathways regulating stress response and life span, including caloric intake, mitochondrial respiration, insulin/IGF-1 (IIS), and JNK (c-Jun N-terminal kinase) signaling. How IIS and JNK signaling cross-talk to defend against diverse stressors contributing to aging is of critical importance but, so far, only poorly understood. In this study, we demonstrate that the adaptor protein SHC-1, the Caenorhabditis elegans homolog of human p52Shc, coordinates mechanisms of stress response and aging. Using genetic and biochemical approaches, we discover that SHC-1 not only opposes IIS but also activates JNK signaling. Loss of shc-1 function results in accelerated aging and enhanced sensitivity to heat, oxidative stress, and heavy metals, whereas expression of human p52Shc rescues the shc-1 mutant phenotype. SHC-1 acts upstream of the insulin/IGF receptor DAF-2 and the PI3 kinase AGE-1 and directly interacts with DAF-2. Moreover, SHC-1 activates JNK signaling by binding to MEK-1 kinase. Both aspects converge on controlling the nuclear translocation and activation of the FOXO transcription factor DAF-16. Our findings establish C. elegans SHC-1 as a critical scaffold that directly cross-connects the two parallel JNK and IIS pathways and help to explain how these signaling cascades cooperate to ascertain normal stress response and life span in C. elegans.