Caspase cleaves Drosophila BubR1 to modulate spindle assembly checkpoint function and lifespan of the organism.

Caspases cleave over 1500 substrates in the human proteome in both lethal and non-lethal scenarios. However, reports of the physiological consequences of substrate cleavage are limited. Additionally, the manner in which caspase cleaves only a subset of substrates in the non-lethal scenario remains to be elucidated.

Enhanced O-GlcNAcylation Mediates Cytoprotection under Proteasome Impairment by Promoting Proteasome Turnover in Cancer Cells.

The proteasome is a therapeutic target in cancer, but resistance to proteasome inhibitors often develops owing to the induction of compensatory pathways. Through a genome-wide siRNA screen combined with RNA sequencing analysis, we identified hexokinase and downstream O-GlcNAcylation as cell survival factors under proteasome impairment. The inhibition of O-GlcNAcylation synergistically induced massive cell death in combination with proteasome inhibition.

Defective induction of the proteasome associated with T-cell receptor signaling underlies T-cell senescence.

The proteasome degradation machinery is essential for a variety of cellular processes including senescence and T-cell immunity. Decreased proteasome activity is associated with the aging process; however, the regulation of the proteasome in CD4 T cells in relation to aging is unclear. Here, we show that defects in the induction of the proteasome in CD4 T cells upon T-cell receptor (TCR) stimulation underlie T-cell senescence.

FAM48A mediates compensatory autophagy induced by proteasome impairment.

Maintaining protein homeostasis is central to cell survival. The ubiquitin-proteasome system and autophagy play pivotal roles in protein quality control through protein degradation. Activities of these degradative pathways are carefully orchestrated, and autophagy is up-regulated during proteasome dysfunction for cellular homeostasis.

Specific Modification of Aged Proteasomes Revealed by Tag-Exchangeable Knock-In Mice.

The proteasome is the proteolytic machinery at the center of regulated intracellular protein degradation and participates in various cellular processes. Maintaining the quality of the proteasome is therefore important for proper cell function. It is unclear, however, how proteasomes change over time and how aged proteasomes are disposed.

PAC1-PAC2 proteasome assembly chaperone retains the core α4-α7 assembly intermediates in the cytoplasm.

The proteasome core particle (CP) is a cytoplasmic and nuclear protease complex and is comprised of two α-rings and two β-rings stacked in order of αββα. The assembly of CP proceeds by ordered recruitment of β-subunits on an α-ring with help of assembly chaperones PAC1-PAC2, PAC3-PAC4, and UMP1. However, the mechanism of α-ring formation remains unsolved.

Nuclear export of ubiquitinated proteins via the UBIN-POST system.

Although mechanisms for protein homeostasis in the cytosol have been studied extensively, those in the nucleus remain largely unknown. Here, we identified that a protein complex mediates export of polyubiquitinated proteins from the nucleus to the cytosol. UBIN, a ubiquitin-associated (UBA) domain-containing protein, shuttled between the nucleus and the cytosol in a CRM1-dependent manner, despite the lack of intrinsic nuclear export signal (NES).

Ubiquitin-Binding Protein CG5445 Suppresses Aggregation and Cytotoxicity of Amyotrophic Lateral Sclerosis-Linked TDP-43 in Drosophila.

Ubiquitin-mediated protein degradation plays essential roles in proteostasis and is involved in the pathogenesis of neurodegenerative diseases in which ubiquitin-positive aberrant proteins accumulate. However, how such aberrant proteins are processed inside cells has not been fully explored. Here, we show that the product of , a previously uncharacterized gene, prevents the accumulation of aggregate-prone ubiquitinated proteins.

A small-molecule compound inhibits a collagen-specific molecular chaperone and could represent a potential remedy for fibrosis.

Fibrosis can disrupt tissue structure and integrity and impair organ function. Fibrosis is characterized by abnormal collagen accumulation in the extracellular matrix. Pharmacological inhibition of collagen secretion therefore represents a promising strategy for the management of fibrotic disorders, such as liver and lung fibrosis.

The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction.

In response to proteasome dysfunction, mammalian cells upregulate proteasome gene expression by activating Nrf1. Nrf1 is an endoplasmic reticulum-resident transcription factor that is continually retrotranslocated and degraded by the proteasome. Upon proteasome inhibition, Nrf1 escapes degradation and is cleaved to become active.

Redundant Roles of Rpn10 and Rpn13 in Recognition of Ubiquitinated Proteins and Cellular Homeostasis.

Intracellular proteins tagged with ubiquitin chains are targeted to the 26S proteasome for degradation. The two subunits, Rpn10 and Rpn13, function as ubiquitin receptors of the proteasome. However, differences in roles between Rpn10 and Rpn13 in mammals remains to be understood.

Sirt1-deficiency causes defective protein quality control.

Protein quality control is an important mechanism to maintain cellular homeostasis. Damaged proteins have to be restored or eliminated by degradation, which is mainly achieved by molecular chaperones and the ubiquitin-proteasome system. The NAD(+)-dependent deacetylase Sirt1 has been reported to play positive roles in the regulation of cellular homeostasis in response to various stresses.

MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination.

McKusick-Kaufman syndrome (MKKS) is a recessively inherited human genetic disease characterized by several developmental anomalies. Mutations in the MKKS gene also cause Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder with pleiotropic symptoms. However, little is known about how MKKS mutations lead to disease.

Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state.

Polyglutamine (polyQ)-expansion proteins cause neurodegenerative disorders including Huntington's disease, Kennedy's disease and various ataxias. The cytotoxicity of these proteins is associated with the formation of aggregates or other conformationally toxic species. Here, we show that the cytosolic chaperonin CCT (also known as TRiC) can alter the course of aggregation and cytotoxicity of huntingtin (Htt)-polyQ proteins in mammalian cells.