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The suppressor of lin-12-like-HMG-CoA reductase degradation 1 (SEL1L-HRD1) complex of the endoplasmic reticulum-associated degradation (ERAD) machinery is a key cellular proteostasis pathway. Although previous studies have shown ERAD as promoting the development and maintenance of many cell types in mice, its importance to human physiology remained undetermined. In two articles in this issue of the JCI, Qi and colleagues describe four biallelic hypomorphic SEL1L and HRD1 variants that were associated with neurodevelopment disorders, locomotor dysfunction, impaired immunity, and premature death in patients. These pathogenic SEL1L-HRD1 variants shine a light on the critical importance of ERAD in humans and pave the way for future studies dissecting ERAD mechanisms in specific cell types.

Stem cells need to be protected from genotoxic and proteotoxic stress to maintain a healthy pool throughout life1–3. Little is known about the proteostasis mechanism that safeguards stem cells. Here we report endoplasmic reticulum-associated degradation (ERAD) as a protein quality checkpoint that controls the haematopoietic stem cell (HSC)–niche interaction and determines the fate of HSCs. The SEL1L–HRD1 complex, the most conserved branch of ERAD4, is highly expressed in HSCs. Deletion of Sel1l led to niche displacement of HSCs and a complete loss of HSC identity, and allowed highly efficient donor-HSC engraftment without irradiation. Mechanistic studies identified MPL, the master regulator of HSC identity5, as a bona fide ERAD substrate that became aggregated in the endoplasmic reticulum following ERAD deficiency. Restoration of MPL signalling with an agonist partially rescued the number and reconstitution capacity of Sel1l-deficient HSCs. Our study defines ERAD as an essential proteostasis mechanism to safeguard a healthy stem cell pool by regulating the stem cell–niche interaction.Xu, Liu, Pen, Zhang et al. demonstrate that the SEL1L–HRD1 complex, which is part of the ERAD protein quality control machinery, safeguards haematopoietic stem cell identity and niche location by ensuring the haematopoietic stem cell surface expression of MPL.

The transcription factor XBP1 is associated with endoplasmic reticulum stress. Glimcher and colleagues show that XBP1 is expressed during eosinophil differentiation and is uniquely required for the production of granule proteins and eosinophil survival. The transcription factor XBP1 has been linked to the development of highly secretory tissues such as plasma cells and Paneth cells, yet its function in granulocyte maturation has remained unknown. Here we discovered an unexpectedly selective and absolute requirement for XBP1 in eosinophil differentiation without an effect on the survival of basophils or neutrophils. Progenitors of myeloid cells and eosinophils selectively activated the endoribonuclease IRE1α and spliced Xbp1 mRNA without inducing parallel endoplasmic reticulum (ER) stress signaling pathways. Without XBP1, nascent eosinophils exhibited massive defects in the post-translational maturation of key granule proteins required for survival, and these unresolvable structural defects fed back to suppress critical aspects of the transcriptional developmental program. Hence, we present evidence that granulocyte subsets can be distinguished by their differential reliance on secretory-pathway homeostasis.

Signals from the pre-T cell receptor and Notch coordinately instruct β-selection of CD4 – CD8 – double negative (DN) thymocytes to generate αβ T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre-selection TCR repertoire given the considerable translational activity imposed by β-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during β-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired mouse αβ T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from Sel1l -deficient thymocytes. In contrast, IRE1α/XBP1 pathway was induced as a compensatory adaptation to alleviate Sel1l -deficiency-induced ER stress. Dual loss of Sel1l and Xbp1 markedly exacerbated the thymic defect. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.

Addiction to oncogene-rewired transcriptional networks is a therapeutic vulnerability in cancer cells, underscoring a need to better understand mechanisms that relay oncogene signals to the transcriptional machinery. Here, using human and mouse T cell acute lymphoblastic leukemia (T-ALL) models, we identify an essential requirement for the endosomal sorting complex required for transport protein CHMP5 in T-ALL epigenetic and transcriptional programming. CHMP5 is highly expressed in T-ALL cells where it mediates recruitment of the coactivator BRD4 and the histone acetyl transferase p300 to enhancers and super-enhancers that enable transcription of T-ALL genes. Consequently, CHMP5 depletion causes severe downregulation of critical T-ALL genes, mitigates chemoresistance and impairs T-ALL initiation by oncogenic NOTCH1 in vivo. Altogether, our findings uncover a non-oncogene dependency on CHMP5 that enables T-ALL initiation and maintenance. Cytosolic CHMP5 is known for its primary function in membrane remodelling. Here the authors report that nuclear CHMP5 promotes T cell acute lymphoblastic leukemia initiation and maintenance in part through regulating epigenetic and transcriptional events.

The suppressor of lin-12-like-HMG-CoA reductase degradation 1 (SEL1LHRD1) complex of the endoplasmic reticulum-associated degradation (ERAD) machinery is a key cellular proteostasis pathway. Although previous studies have shown ERAD as promoting the development and maintenance of many cell types in mice, its importance to human physiology remained undetermined. In two articles in this issue of theJCI, Qi and colleagues describe four biallelic hypomorphic SEL1L and HRD1 variants that were associated with neurodevelopment disorders, locomotor dysfunction, impaired immunity, and premature death in patients. These pathogenic SEL1L-HRD1 variants shine a light on the critical importance of ERAD in humans and pave the way for future studies dissecting ERAD mechanisms in specific cell types.

T cell immunity requires the long-term survival of T cells that are capable of recognizing self antigens but are not overtly autoreactive. How this balance is achieved remains incompletely understood. Here we identify a homeostatic mechanism that transcriptionally tailors CD8 coreceptor expression in individual CD8 + T cells to the self-specificity of their clonotypic T cell receptor (TCR). 'Coreceptor tuning' results from interplay between cytokine and TCR signals, such that signals from interleukin 7 and other common γ-chain cytokines transcriptionally increase CD8 expression and thereby promote TCR engagement of self ligands, whereas TCR signals impair common γ-chain cytokine signaling and thereby decrease CD8 expression. This dynamic interplay induces individual CD8 + T cells to express CD8 in quantities appropriate for the self-specificity of their TCR, promoting the engagement of self ligands, yet avoiding autoreactivity.

Key Points Developing CD4 + CD8 + double positive (DP) thymocytes differentiate either into CD4 + helper or CD8 + cytotoxic T cells, depending on the MHC-restriction specificity of their T-cell receptor (TCR). Classical models of CD4/CD8-lineage choice share the perspective that lineage choice occurs in thymocytes that express both Cd4 and Cd8 at the mRNA level (that is, transcriptionally Cd4 + Cd8 + ) and results in the termination of transcription of one or the other co-receptor molecule as a consequence of the same TCR signals that mediate positive selection. Classical models are either stochastic or instructive, and experimental testing of these models has been extensive. However, crucial presumptions made by each classical model (stochastic selection, strength-of-signal or duration-of-signal models) have been experimentally contradicted. The kinetic signalling model of CD4/CD8-lineage choice differs in various respects from all classical models, as it postulates that TCR-signalled DP thymocytes first transiently terminate Cd8 gene expression and convert into Cd4 + Cd8 − intermediate cells in which CD4/CD8-lineage choices are then made. Thus, positive selection and lineage choice are sequential events. CD4/CD8-lineage choice is determined in Cd4 + Cd8 − intermediate cells by whether TCR-mediated positive selection signalling persists or ceases in the absence of Cd8 gene expression. Persistent TCR signalling drives CD4 + T-cell development, whereas disrupted TCR signalling permits signalling by interleukin-7 and other common cytokine-receptor γ-chain cytokines that drive CD8 + T-cell development. Recent advances in the molecular events that occur during CD4/CD8-lineage choice have identified a series of nuclear factors, including Th-POK (T-helper-inducing POZ/Kruppel-like factor), RUNX3 (runt-related transcription factor 3), TOX (thymus high-mobility group box protein) and GATA3 (GATA-binding protein 3), that are crucially involved in T-cell-lineage-fate determination. It is possible to integrate the activity of these nuclear factors into the kinetic signalling model to achieve an integrated picture of CD4/CD8-lineage choice on both a cellular and molecular level. What determines whether a developing thymocyte becomes a CD4 + or CD8 + T cell has been an issue of longstanding debate. Here, the authors review the models that have been proposed to explain CD4/CD8-lineage choice and update us on the environmental and transcription factors that might mediate this decision. Following successful gene rearrangement at αβ T-cell receptor (TCR) loci, developing thymocytes express both CD4 and CD8 co-receptors and undergo a life-or-death selection event, which is known as positive selection, to identify cells that express TCRs with potentially useful ligand specificities. Positively selected thymocytes must then differentiate into either CD4 + helper T cells or CD8 + cytotoxic T cells, a crucial decision known as CD4/CD8-lineage choice. In this Review, we summarize recent advances in our understanding of the cellular and molecular events involved in lineage-fate decision and discuss them in the context of the major models of CD4/CD8-lineage choice.

Immature thymocytes are bipotential cells that are signalled during positive selection to become either helper‐ or cytotoxic‐lineage T cells. By tracking expression of lineage determining transcription factors during positive selection, we now report that the Cd8 coreceptor gene locus co‐opts any coreceptor protein encoded within it to induce thymocytes to express the cytotoxic‐lineage factor Runx3 and to adopt the cytotoxic‐lineage fate, findings we refer to as ‘coreceptor gene imprinting’. Specifically, encoding CD4 proteins in the endogenous Cd8 gene locus caused major histocompatibility complex class II‐specific thymocytes to express Runx3 during positive selection and to differentiate into CD4 + cytotoxic‐lineage T cells. Our findings further indicate that coreceptor gene imprinting derives from the dynamic regulation of specific cis Cd8 gene enhancer elements by positive selection signals in the thymus. Thus, for coreceptor‐dependent thymocytes, lineage fate is determined by Cd4 and Cd8 coreceptor gene loci and not by the specificity of T‐cell antigen receptor/coreceptor signalling. This study identifies coreceptor gene imprinting as a critical determinant of lineage fate determination in the thymus. Double‐positive (CD4 + CD8 + ) thymocytes differentiate into CD4 + helper T cells and CD8 + cytotoxic T cells. A knock‐in approach replacing CD8‐coding sequences with CD4 cDNA shows that it is the expression kinetics of CD8, and not the identity of the coreceptor, that governs thymocyte‐lineage fate.

This study finds that triple-negative breast cancers (TNBC) show an increased basal level of endoplasmic reticulum stress and activation of the XBP1 branch of the unfolded protein response; furthermore, XBP1 promotes tumour formation of TNBC cell lines by interacting with and regulating HIF1α. Role of XBP1 in aggressive breast cancer Laurie Glimcher and colleagues report that in triple-negative breast cancers (TNBCs), the tumour cells show an increased basal level of endoplasmic reticulum stress and activation of the XBP1 branch of the unfolded protein response, a major cellular stress response pathway in the tumour microenvironment. TNBC tumours lack receptors for oestrogen, progesterone and HER2, making them recalcitrant to many drugs through an absence of targets. The authors go on to show that XBP1 promotes tumour formation in TNBC cell lines by interacting with and regulating HIF1α in the absence of hypoxia. This study highlights an important link between two major stress pathways in TNBCs and suggests possible therapeutic interventions for this aggressive form of breast cancer. Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization 1 . One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2 ) and its substrate XBP1 (ref. 3 ). Previous studies report UPR activation in various human tumours 4 , 5 , 6 , but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)—a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)—is a highly aggressive malignancy with limited treatment options 7 , 8 . Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44 high CD24 low population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs 9 , 10 . Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.