TRIM RING finger proteins have been shown to play an important role in cancerogenesis, in the pathogenesis of some human hereditary disorders, and in the defense against viral infection, but the function of the majority of TRIM proteins remains unknown. Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination. Additionally, we show that mice deficient in TRIM2 have increased NF-L level in axons and NF-L-filled axonal swellings in cerebellum, retina, spinal cord, and cerebral cortex. The axonopathy is followed by progressive neurodegeneration accompanied by juvenile-onset tremor and ataxia. Our results demonstrate that TRIM2 is an ubiquitin ligase and point to a mechanism regulating NF-L metabolism through an ubiquitination pathway that, if deregulated, triggers neurodegeneration.RING finger protein ͉ axonopathy ͉ ataxia ͉ ubiquitination U biquitination of a protein can influence its stability, interactions, activity, or intracellular localization. Three main enzyme families are involved in ubiquitination: ubiquitin activating enzymes, ubiquitin conjugating enzymes, and ubiquitin ligases. Correct localization, timing and specificity of the ubiquitination reaction are ensured mainly by ubiquitin ligases (E3s). RING finger E3s are the most abundant E3 class, characterized by the presence of the cysteine-rich RING finger domain (1). Tripartite (TRIM) RING finger proteins have been defined based on their conserved modular structure (RING finger, B-box, coiled-coil domains) as a subgroup of the RING finger proteins (2). Despite their well conserved modular structure, no common biological role has yet been discovered for TRIM proteins. Recently, some members of the TRIM family have been identified as ubiquitin ligases, involved in cancerogenesis and the defense against viral infection (3, 4). Several human diseases have been linked to mutant RING finger and TRIM E3s. Mutations in the RING finger protein parkin have been shown to trigger a juvenile form of Parkinson's disease (PD) (5). A mutant TRIM37 has been found to cause mulibrey nanism in human (6) and translocation of the TRIM gene pml has been identified in patients suffering from acute promyelocytic leukemia (3). The function of the most of TRIM proteins has not yet been discovered.TRIM2, highly expressed in the nervous system, has been linked to neuronal activity because its expression in hippocampus correlates with the activity of NMDA receptor (7). In addition, it has been shown to interact with the unconventional motor protein myosin V (7). In the present study, we demonstrate that TRIM2 is an ubiquitin ligase with its activity confined to the RING finger domain. In addition, we show that TRIM2 interacts with the neurofilament light subunit (NF-L) and that ubiquitination of NF-L significantly increases after expression of the full-length TRIM2, but not TRIM2 ligase dead muta...

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Maternal neuronal signaling has been reported to program adaptive changes in offspring physiology in diverse organisms [1, 2]. However, the mechanisms for the inheritance of adaptive maternal effects through the germline are largely unknown. In the nematode Auanema freiburgensis, stress-resistance and sex of the offspring depend on environmental cues experienced by the mother. Maternal sensing of high population densities results in the production of stress-resistant larvae (dauers) that develop into hermaphrodites. Ablation of the maternal ASH chemosensory neurons results only in non-dauer offspring that develop into males or females. High population densities correlate with changes in the methylation status of H3K4 and H3K9 in the maternal germline. Inhibition of JMJD histone demethylases prevents mothers from producing dauers and hermaphrodite offspring in high-density conditions. Our results demonstrate a case of soma-to-germline transmission of environmental information that influences the phenotype of the following generation through changes in histone modifications of the maternal germline.HighlightsHigh population density leads to the production of hermaphrodite offspring.The ASH neuron in the hermaphrodite mother senses population density.Histone modifications in the maternal germline correlate with the sex of offspring.Inhibition of histone demethylases results in female offspring in all conditions.

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