The N-degron pathway is a degradative system in which the N-terminal residues of proteins modulate the half-lives of proteins and other cellular materials. The majority of amino acids in the genetic code have the potential to induce cis or trans degradation in diverse processes, which requires selective recognition between N-degrons and cognate N-recognins. Of particular interest is the Cys/N-degron branch, in which the N-terminal cysteine (Nt-Cys) induces proteolysis via either the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome pathway (ALP), depending on physiological conditions. Recent studies provided new insights into the central role of Nt-Cys in sensing the fluctuating levels of oxygen and reactive oxygen species (ROS). Here, we discuss the components, regulations, and functions of the Cys/N-degron pathway.

Detection and conversion of mechanical forces into biochemical signals is known as mechanotransduction. From cells to tissues, mechanotransduction regulates migration, proliferation, and differentiation in processes such as immune responses, development, and cancer progression. Mechanosensitive structures such as integrin adhesions, the actin cortex, ion channels, caveolae, and the nucleus sense and transmit forces. In vitro approaches showed that mechanosensing is based on force-dependent protein deformations and reorganizations. However, the mechanisms in cells remained unclear since cell imaging techniques lacked molecular resolution. Thanks to recent developments in super-resolution microscopy (SRM) and molecular force sensors, it is possible to obtain molecular insight of mechanosensing in live cells. We discuss how understanding of molecular mechanotransduction was revolutionized by these innovative approaches, focusing on integrin adhesions, actin structures, and the plasma membrane.

Pharmacology-based methods that promote antitumor immunity have the potential to be highly efficacious while avoiding the systemic cytotoxicity associated with traditional chemotherapies. Activation of type I interferon (IFN) signaling in antigen-presenting cell types [e.g., macrophages and dendritic cells (DCs)] is critical, if not essential, for inducing a tumor-specific adaptive immune response, including the activation of cytolytic CD8 T cells. In the context of promoting antitumor immunity, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway has emerged as a principal regulator of essential type I IFN signaling. As such, STING represents a highly attractive target for developing a first-in-class immunotherapy, albeit one with a potential for significant cell type- and downstream pathway-dependent on-target toxicities, as well as conceivable pharmacogenomic liabilities.

Adipose tissue signals to brain, liver, and muscles to control whole body metabolism through secreted lipid and protein factors as well as neurotransmission, but the mechanisms involved are incompletely understood. Adipocytes sequester triglyceride (TG) in fed conditions stimulated by insulin, while in fasting catecholamines trigger TG hydrolysis, releasing glycerol and fatty acids (FAs). These antagonistic hormone actions result in part from insulin's ability to inhibit cAMP levels generated through such G-protein-coupled receptors as catecholamine-activated β-adrenergic receptors. Consistent with these antagonistic signaling modes, acute actions of catecholamines cause insulin resistance. Yet, paradoxically, chronically activating adipocytes by catecholamines cause increased glucose tolerance, as does insulin. Recent results have helped to unravel this conundrum by revealing enhanced complexities of these hormones' signaling networks, including identification of unexpected common signaling nodes between these canonically antagonistic hormones.

There is now a consensus that mitochondria are important tumor drivers, sophisticated biological machines that can engender a panoply of key disease traits. How this happens, however, is still mostly elusive. The opinion presented here is that what cancer exploits are not the normal mitochondria of oxygenated and nutrient-replete tissues, but the unfit, damaged, and dysfunctional organelles generated by the hostile environment of tumor growth. These 'ghost' mitochondria survive quality control and thwart cell death to relay multiple comprehensive 'danger signals' of metabolic starvation, cellular stress, and reprogrammed gene expression. The result is a new, treacherous cellular phenotype, proliferatively quiescent but highly motile, that enables tumor cell escape from a threatening environment and colonization of distant, more favorable sites (metastasis).

Ribosome-associated protein quality control (RQC) is a protein surveillance mechanism that eliminates defective nascent polypeptides. The E3 ubiquitin ligase, Ltn1, is a key regulator of RQC that targets substrates for ubiquitination. Argonaute proteins (AGOs) are central players in miRNA-mediated gene silencing and have recently been shown to also regulate RQC by facilitating Ltn1. Therefore, AGOs directly coordinate post-transcriptional gene silencing and RQC, ensuring efficient gene silencing. We summarize the principles of RQC and the functions of AGOs in miRNA-mediated gene silencing, and discuss how AGOs associate with the endoplasmic reticulum (ER) to assist Ltn1 in controlling RQC. We highlight that RQC not only eliminates defective nascent polypeptides but also removes unwanted protein products when AGOs participate.

The MYC protooncogene functions as a universal amplifier of transcription through interaction with numerous factors and complexes that regulate almost every cellular process. However, a comprehensive model that explains MYC's actions and the interplay governing the complicated dynamics of components of the transcription and replication machinery is still lacking. Here, we review the potency of MYC as an oncogenic driver and how it regulates the broad spectrum of complexes (effectors and regulators). We propose a 'hand-over model' for differential partitioning and trafficking of unstructured MYC via a loose interaction network between various gene-regulatory complexes and factors. Additionally, the article discusses how unstructured-MYC energetically favors efficient modulation of the energy landscape of the transcription cycle.