Highlights d Enlarged thymus in K5D1 mice produces immunocompetent and self-tolerant T cells d Enlarged thymus in K5D1 mice enables proteomic analysis of cTECs and mTECs d Trans-omics profiles identify signature molecules that characterize cTECs and mTECs d b5t deficiency specifically affects proteasomal subunit composition in cTECs

The thymus is an organ that produces functionally competent T cells that protect us from pathogens and malignancies. Foxn1 is a transcription factor that is essential for thymus organogenesis; however, the direct target for Foxn1 to actuate thymic T-cell production is unknown. Here we show that a Foxn1-binding cis-regulatory element promotes the transcription of β5t, which has an essential role in cortical thymic epithelial cells to induce positive selection of functionally competent CD8+ T cells. A point mutation in this genome element results in a defect in β5t expression and CD8+ T-cell production in mice. The results reveal a Foxn1-β5t transcriptional axis that governs CD8+ T-cell production in the thymus.

The 26S proteasome is a multisubunit complex that catalyzes the degradation of ubiquitinated proteins. The proteasome comprises 33 distinct subunits, all of which are essential for its function and structure. Proteasomes are necessary for various biological processes in cells; therefore, precise regulation of proteasome expression and activity is essential for maintaining cellular health and function. Two decades of research revealed that transcription factors such as Rpn4 and Nrf1 control expression of proteasomes. In this review, we focus on the current understanding and recent findings on the mechanisms underlying the regulation of proteasome expression, as well as the translational regulation of proteasomes.

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. Proteasome dysfunction promotes senescence‐associated phenotypes, including defective proliferation, cytokine production and increased levels of PD‐1+ CD44High CD4+ T cells. Proteasome induction by TCR signaling via MEK‐, IKK‐ and calcineurin‐dependent pathways is attenuated with age and decreased in PD‐1+ CD44High CD4+ T cells, the proportion of which increases with age. Our results indicate that defective induction of the proteasome is a hallmark of CD4+ T‐cell senescence.

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. However, the mechanism by which proteasome impairment induces compensatory autophagy has remained largely elusive. Here, we show that FAM48A mediates autophagy induction during proteasome inhibition. FAM48A is degraded by the proteasome and accumulates in cells by proteasome inhibition. Knockdown of FAM48A led to defective induction of autophagy during proteasome inhibition and accompanied by defective localization of Atg9 on recycling endosomes. Our results indicate that FAM48A is a kind of sensor that is required for compensatory autophagy induction upon proteasome impairment. K E Y W O R D S autophagy, proteasome 560 | Genes to Cells ARATA eT Al.