By systematically profiling the sedimentation-rates of lncRNAs on glycerol-gradients, 22 sub-groups of human phagocyte lncRNAs could be discriminated, cosedimenting with protein-components of diverse subcellular machineries. Interestingly, a prominent subgroup, comprising dozens of lncRNAs, was found to comigrate with components of the ubiquitin-proteasome system (UPS) [
16]. The UPS comprises a network of ubiquitin-ligases, ubiquitinated proteins, ubiquitin-readers and the large proteasome assemblies, involved in ubiquitination-dependent protein processing and decay [
81]. Ubiquitination can furthermore serve as a regulatory modification, controlling protein-activation and complex formation [
81]. Recently, several cytoplasmic lncRNAs have been functionally linked to the UPS system. In innate immune cells, for instance, the signalling cascades activated in response to infectious agents are tightly controlled by ubiquitination and lncRNAs [
82,
83]. Detection of bacterial lipopolysaccharides by the prototypic plasma membrane spanning innate immune receptor TLR4 activates a complex signalling cascade, resulting in proinflammatory gene expression through the TLR4-MyD88 pathway and in type I interferon production through the TLR4-TRIF pathway [
84]. Mirt2 is a TLR4-induced lncRNA in murine macrophages, which functions as a negative regulator of the TLR-MyD88 pathway. Mechanistically, Mirt2 binds to the TLR-MyD88 pathway component TRAF6 to block TRAF6 autoubiquitination and thus signaling pathway progression [
85]. Production of antiviral and antibacterial interferons downstream of TLR4 in human cells depends on TLR4-induced lncRNA MaIL1, which promotes ubiquitination of the signalling adapter OPTN and thus progression of TLR4-TRIF signalling [
16]. MaIL1 also controls the formation of cellular foci composed of ubiquitin-associated OPTN, potentially representing subcellular signalling protein platforms [
16]. Similarly, murine lncRNA lnczc3h7a is upregulated upon viral infection and promotes TRIM25-dependent ubiquitination of the cytosolic antiviral innate immune-receptor RigI and thus downstream signal transduction and interferon activation [
44]. Other lncRNAs regulate protein ubiquitination in the adaptive immune system to control antiviral and antitumour defense. In CD4+ T cells, for instance, LncRNA NRON was found to suppress viral replication by destabilizing viral transactivator protein Tat. Mechanistically, NRON couples the Tat protein to components of the ubiquitin-proteasome system, such as CUL4B and PSMD11, thus promoting Tat degradation [
86]. In the context of hepatocellular carcinoma, upregulation of epidermal growth factor receptor (EGFR) expression in regulatory T cells (Tregs) was found to contribute to tumorigenesis [
87]. An lncRNA, lnc-EGFR, was found to inhibit EGFR ubiquitination by the E3-ligase c-CBL, thereby contributing to EGFR up-regulation in T cells and Treg dependent immunosuppression [
87]. Beyond the immune system, several cytoplasmic lncRNAs were found to contribute to tumorigenesis through association with ubiquitin-ligases. In glioma cells, lncRNA RP11-732M18.3 interacts with the multifunctional 14-3-3β/α proteins in the cytoplasm and recruits the ubiquitin-conjugating enzyme UBE2E1. This RNP complex promotes the ubiquitin-proteasome-dependent degradation of the cell cycle arrest inducing p21 protein, thereby contributing to cancerogenesis [
88]. LncRNA BDNF-AS was reported to promote breast cancer progression by functioning as a scaffold RNA, supporting RNH1 ubiquitination by the E3 ligase TRIM21 and thus RNH1 degradation. This relieves mTOR mRNA suppression by RNH1 and promotes cell-proliferation associated mTOR signalling and thus cancer progression [
89]. In non-small-cell lung cancer cells, lncRNA MetaLnc9 was found to promote cell migration and invasion. Mechanistically, MetaLnc9 interacts with and prevents from PGK1 kinase ubiquitination, thereby fostering AKT/mTOR signalling [
90]. Further lncRNAs are likely involved in ubiquitination-dependent cellular processes and pathomechanisms, as indicated by the cosedimentation of dozens of lncRNAs with UPS components [
16]. Of note, ubiquitinated protein substrates and ubiquitin-adapters can form aggresomes and inclusion bodies in the cytoplasm [
91]. Failure to remove such aggregates by the proteasomal or autophagic pathways is involved in diseases such as amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) [
92]. LncRNA MaIL1 seems to be involved in the formation of ubiquitin-reader aggregates under conditions of proteasome inhibition [
16]. It remains to be investigated, whether the dynamic formation and resolution of cytoplasmic ubiquitin-associated protein aggregates under homeostatic and disease conditions depend on further lncRNAs.