SHIP-1 Regulates the Differentiation and Function of Tregs via Inhibiting mTORC1 Activity

Cell metabolism is crucial for orchestrating the differentiation and function of regulatory T cells (Tregs). However, the underlying signaling mechanism that coordinates cell metabolism to regulate Treg activity is not completely understood. As a pivotal molecule in lipid metabolism, the role of SHIP-1 has been studied extensively in B cells and CD4 T cells, yet its regulatory role in Tregs remains unknown. In this study, we generated “SHIP-1 KO mice” that have SHIP-1 specifically deleted in regulatory T cells by crossing Foxp3YFP-cre mice with SHIP-1fl/fl mice. Surprisingly, SHIP-1 KO mice had severe autoimmunity with increased Tregs in the thymus and disrupted peripheral T cell homeostasis. Mechanistically, CD4Cre SHIP-1flox/flox mice were found to have increased Treg precursors and SHIP-1 KO Tregs had reduced migration and stability, which caused decreased Tregs in the spleen. Additionally, the suppressive function of Tregs from SHIP-1 KO mice was diminished, along with their promotion of anti-tumor immunity. Interestingly, the PI3K-mTORC1, but not mTORC2, signaling axis was enhanced in SHIP-1 KO Tregs. In vivo treatment of SHIP-1 KO mice with rapamycin rescued the abnormal Treg percentages and peripheral T cell homeostasis, as well as Treg suppressive function. Furthermore, the treatment of wild-type mice with SHIP-1 inhibitor enhanced anti-tumor activity. Our study has revealed a previously unrecognized underlying function of SHIP-1 in Tregs, which highlights the SHIP-1-PI3K-mTORC1 axis that regulates Treg differentiation and function.

Emerging Lysosomal Functions for Photoreceptor Cell Homeostasis and Survival

Lysosomes are membrane-bound cell organelles that respond to nutrient changes and are implicated in cell homeostasis and clearance mechanisms, allowing effective adaptation to specific cellular needs. The relevance of the lysosome has been elucidated in a number of different contexts. Of these, the retina represents an interesting scenario to appreciate the various functions of this organelle in both physiological and pathological conditions. Growing evidence suggests a role for lysosome-related mechanisms in retinal degeneration. Abnormal lysosomal activation or inhibition has dramatic consequences on photoreceptor cell homeostasis and impacts extensive cellular function, which in turn affects vision. Based on these findings, a series of therapeutic methods targeting lysosomal processes could offer treatment for blindness conditions. Here, we review the recent findings on membrane trafficking, subcellular organization, mechanisms by which lysosome/autophagy pathway impairment affects photoreceptor cell homeostasis and the recent advances on developing efficient lysosomal-based therapies for retinal disorders.

Ubiquitination and SUMOylation: protein homeostasis control over cancer

Ubiquitination and SUMOylation are two essential components of the ubiquitination proteasome system playing fundamental roles in protein homeostasis maintenance and signal transduction, perturbation of which is associated with tumorigenesis. By comparing the mechanisms of ubiquitination and SUMOylation, assessing their crosstalk, reviewing their differential associations with cancer and identifying unaddressed yet important questions that may lead the field trend, this review sheds light on the similarities and differences of ubiquitination and SUMOylation toward the improved harnessing of both post-translational modification machineries, as well as forecasts novel onco-therapeutic opportunities through cell homeostasis control.

Proteoglycans and Glycosaminoglycans in Stem Cell Homeostasis and Bone Tissue Regeneration

Stem cells maintain a subtle balance between self-renewal and differentiation under the regulatory network supported by both intracellular and extracellular components. Proteoglycans are large glycoproteins present abundantly on the cell surface and in the extracellular matrix where they play pivotal roles in facilitating signaling transduction and maintaining stem cell homeostasis. In this review, we outline distinct proteoglycans profiles and their functions in the regulation of stem cell homeostasis, as well as recent progress and prospects of utilizing proteoglycans/glycosaminoglycans as a novel glycomics carrier or bio-active molecules in bone regeneration.

Lymph node formation and B cell homeostasis require IKK-α in distinct endothelial cell–derived compartments

Global inactivation of IκB kinase (IKK)-α results in defective lymph node (LN) formation and B cell maturation, and loss of IKK-α–dependent noncanonical NF-κB signaling in stromal organizer and hematopoietic cells is thought to underlie these distinct defects. We previously demonstrated that this pathway is also activated in vascular endothelial cells (ECs). To determine the physiologic function of EC-intrinsic IKK-α, we crossed IkkαF/F mice with Tie2-cre or Cdh5-cre mice to ablate IKK-α in ECs. Notably, the compound defects of global IKK-α inactivation were recapitulated in IkkαTie2 and IkkαCdh5 mice, as both lacked all LNs and mature follicular and marginal zone B cell numbers were markedly reduced. However, as Tie2-cre and Cdh5-cre are expressed in all ECs, including blood forming hemogenic ECs, IKK-α was also absent in hematopoietic cells (HC). To determine if loss of HC-intrinsic IKK-α affected LN development, we generated IkkαVav mice lacking IKK-α in only the hematopoietic compartment. While mature B cell numbers were significantly reduced in IkkαVav mice, LN formation was intact. As lymphatic vessels also arise during development from blood ECs, we generated IkkαLyve1 mice lacking IKK-α in lymphatic ECs (LECs) to determine if IKK-α in lymphatic vessels impacts LN development. Strikingly, while mature B cell numbers were normal, LNs were completely absent in IkkαLyve1 mice. Thus, our findings reveal that IKK-α in distinct EC-derived compartments is uniquely required to promote B cell homeostasis and LN development, and we establish that LEC-intrinsic IKK-α is absolutely essential for LN formation.

Perfluorooctanesulfonic acid modulates barrier function and systemic T cell homeostasis during intestinal inflammation

The intestinal epithelium is continuously exposed to deleterious environmental factors which might cause aberrant immune responses leading to inflammatory disorders. However, what environmental factors might contribute to disease are yet poorly understood. Here, to overcome the lack of in vivo models suitable for screening of environmental factors we used zebrafish reporters of intestinal inflammation. Using zebrafish, we interrogated the immunomodulatory effects of polyfluoroalkyl substances (PFAS), which have been positively associated with ulcerative colitis incidence. Exposure with perfluorooctanesulfonic acid (PFOS) during TNBS-induced inflammation enhances the expression of proinflammatory cytokines as well as neutrophil recruitment to the intestine of zebrafish larvae, which was validated in TNBS-induced colitis mice models. Moreover, PFOS exposure in mice undergoing colitis resulted in neutrophil-dependent increased intestinal permeability and enhanced PFOS translocation into circulation. Finally, this was associated with a neutrophil dependent expansion of systemic CD4+ T cells. Thus, our results indicate that PFOS worsens inflammation-induced intestinal damage with disruption of T cell homeostasis beyond the gut and provides a novel in vivo toolbox to screen for pollutants affecting intestinal homeostasis.