Neddylation, a ubiquitylation-like post-translational modification, is catalyzed by a cascade composed of three enzymes: E1 activating enzyme, E2 conjugating enzyme, and E3 ligase with cullins as physiological substrates. Specifically, neddylation E2 UBE2M couples with E3 RBX1 to neddylate cullins 1-4, whereas neddylation E2 UBE2F couples with E3 RBX2/SAG to neddylate cullin 5, leading to activation of CRL1-4 (Cullin-RING ligases 1-4) and CRL5, respectively. While over-activation of the neddylation-CRLs axis occurs frequently in many human cancers, how neddylation-CRLs regulate the function of immune cells, particularly Treg cells was previously unknown. To this end, we recently performed Treg selective knockout of two neddylation E2s and two E3s, individually, driven by Foxp3-Cre, and found that while the Ube2f-Sag E2/E3 pair plays a minimal role, if any, the Ube2m-Rbx1 pair is essential for the maintenance of Treg functionality, since their deletion triggers robust inflammatory response with autoimmune phenotypes. Milder phenotype severity upon Treg KO of upstream Ube2m than that of downstream Rbx1 strongly suggested that Rbx1 regulates Treg function in a manner dependent and independent of neddylation.

Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, elicits adaptive responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import.

The behavior of somatic stem cells is regulated by their niche. Interaction between hematopoietic stem cells (HSCs) and their niches are a representative model to understand stem cell-niche interplay. Here, we provide an overview of crosstalk between HSCs and their niches in bone marrow and extramedullary organs following the life journey of HSCs from emergence, development, maturation until aging. We highlight the unique differences of HSC niches in different life stages within various organs focusing on recent literature to propose new speculations and hypotheses.

Paleoneuranatomy is an emerging subfield of paleontological research with great potential for the study of evolution. However, the interpretation of fossilized nervous tissues is a difficult task and presently lacks a rigorous methodology. We critically review here cases of neural tissue preservation reported in Cambrian arthropods, following a set of fundamental paleontological criteria for their recognition. These criteria are based on a variety of taphonomic parameters and account for morphoanatomical complexity. Application of these criteria shows that firm evidence for fossilized nervous tissues is less abundant and detailed than previously reported, and we synthesize here evidence that has stronger support. We argue that the vascular system, and in particular its lacunae, may be central to the understanding of many of the fossilized peri-intestinal features known across Cambrian arthropods. In conclusion, our results suggest the need for caution in the interpretation of evidence for fossilized neural tissue, which will increase the accuracy of evolutionary scenarios.

The pore-forming BCL-2 family proteins are effectors of mitochondrial poration in apoptosis initiation. Two atypical effectors-BOK and truncated BID (tBID)-join the canonical effectors BAK and BAX. Gene knockout revealed developmental phenotypes in the absence the effectors, supporting their roles in vivo. During apoptosis effectors are activated and change shape from dormant monomers to dynamic oligomers that associate with and permeabilize mitochondria. BID is activated by proteolysis, BOK accumulates on inhibition of its degradation by the E3 ligase gp78, while BAK and BAX undergo direct activation by BH3-only initiators, autoactivation, and crossactivation. Except tBID, effector oligomers on the mitochondria appear as arcs and rings in super-resolution microscopy images. The BH3-in-groove dimers of BAK and BAX, the tBID monomers, and uncharacterized BOK species are the putative building blocks of apoptotic pores. Effectors interact with lipids and bilayers but the mechanism of membrane poration remains elusive. I discuss effector-mediated mitochondrial poration.

Interferons (IFNs) are a diverse group of cytokines whose potent antitumor effects have piqued the interest of scientists for decades. Some of the most sustained clinical accomplishments have been in the field of myeloproliferative neoplasms (MPNs). Here, we discuss how both historical and novel breakthroughs in our understanding of IFN function may lead to more effective therapies for MPNs. The particular relevance and importance of modulating the novel IFN-regulated ULK1 pathway to optimize IFN responses is highlighted.