Endoplasmic reticulum (ER)-associated degradation (ERAD) and the unfolded protein response (UPR) are two key quality-control machineries in the cell. ERAD is responsible for the clearance of ...misfolded proteins in the ER for cytosolic proteasomal degradation, while UPR is activated in response to the accumulation of misfolded proteins. It has long been thought that ERAD is an integral part of UPR because expression of many ERAD genes is controlled by UPR; however, recent studies have suggested that ERAD has a direct role in controlling the protein turnover and abundance of IRE1α, the most conserved UPR sensor. Here, we review recent advances in our understanding of IRE1α activation and propose that UPR and ERAD engage in an intimate crosstalk to define folding capacity and maintain homeostasis in the ER.
The UPR sensor IRE1α and SEL1L-HRD1 ERAD are the two most conserved branches of ER quality-control mechanisms.
IRE1α activation is controlled by different modulators, such as newly identified ERdj4, HSP47, and SEL1L-HRD1 ERAD.
SEL1L-HRD1 ERAD targets IRE1α for proteasomal degradation to restrain IRE1α signaling under basal condition.
Crosstalk between UPR and ERAD is critical for the maintenance of ER homeostasis under physiological and pathological conditions.
Abstract
Apoptosis has long been recognized as a mechanism that kills the cancer cells by cytotoxic drugs. In recent years, studies have proved that pyroptosis can also shrink tumors and inhibit ...cells proliferation. Both apoptosis and pyroptosis are caspase-dependent programmed cell death pathways. Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death. When GSDME is highly expressed, the active caspase-3 cuts it and releases the N-terminal domain to punch holes in the cell membrane, resulting in cell swelling, rupture, and death. When the expression of GSDME is low, it will lead to the classical mechanism of tumor cell death, which is apoptosis. More interestingly, researchers have found that GSDME can also be located upstream of caspase-3, connecting extrinsic, and intrinsic apoptotic pathways. Then, promoting caspase-3 activation, and forming a self-amplifying feed-forward loop. GSDME-mediated pyroptosis is correlated with the side effects of chemotherapy and anti-tumor immunity. This article mainly reviews the caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer, to provide new strategies and targets for cancer treatment.
Cysteinyl aspartate specific proteinase (Caspase)‐8 has long been considered a promoter of apoptosis and part of the mechanism by which cytotoxic drugs kill cancer cells. With the continuous ...exploration of the types of programmed cell death, an increasing number of studies have confirmed that caspase‐8 plays an important role in cancer. Recently, scholars have proposed the term “PANoptosis,” which mainly includes three programmed cell death modes, namely pyroptosis, apoptosis and necroptosis. In addition to mediating endogenous apoptotic pathways, caspase‐8 can also participate in the cleavage of gasdermin (GSDM) family proteins to induce pyroptosis. Furthermore, the expression of enzymatically inactive caspase‐8 (C362S) can cause embryonic lethality and inflammatory tissue destruction in mice by inducing necroptosis and pyroptosis. Therefore, the activation and deletion of caspase‐8 enzyme activity, as well as the knockout of the coding gene, are closely related to “PANoptosis.” In addition, caspase‐8 can also improve the tumor microenvironment and enhance tumor antiimmunity. Studies have shown that caspase‐8 is also associated with tumor growth and invasion, angiogenesis and metastasis, therapeutic resistance and poor clinical outcomes. Therefore, it is very important to measure the cancer‐promoting and anticancer effects of caspase‐8 and find a balance, and to study its role in the effect of “PANoptosis” in depth. This article reviews the role of caspase‐8 in “PANoptosis” in cancer to provide new strategies and targets for cancer.
Pyroptosis refers to the process of gasdermin (GSDM)‐mediated programmed cell death (PCD). Our understanding of pyroptosis has expanded beyond cells and is known to involve extracellular responses. ...Recently, there has been an increasing interest in pyroptosis due to its emerging role in activating the immune system. In the meantime, pyroptosis‐mediated therapies, which use the immune response to kill cancer cells, have also achieved notable success in a clinical setting. In this review, we discuss that the immune response induced by pyroptosis activation is a double‐edged sword that affects all stages of tumorigenesis. On the one hand, the activation of inflammasome‐mediated pyroptosis and the release of pyroptosis‐produced cytokines alter the immune microenvironment and promote the development of tumors by evading immune surveillance. On the other hand, pyroptosis‐produced cytokines can also collect immune cells and ignite the immune system to improve the efficiency of tumor immunotherapies. Pyroptosis is also related to some immune checkpoints, especially programmed death‐1 (PD‐1) or programmed death‐ ligand 1 (PD‐L1). In this review, we mainly focus on our current understanding of the interplay between the immune system and tumors that process through pyroptosis, and debate their use as potential therapeutic targets.
The immune response induced by pyroptosis activation is a double‐edged sword that affects all stages of tumorigenesis. On the one hand, the activation of inflammasome‐mediated pyroptosis and the release of pyroptosis‐produced cytokines alter the immune microenvironment and promote the development of tumors by evading immune surveillance. On the other hand, pyroptosis‐produced cytokines can also collect immune cells and ignite the immune system to improve the efficiency of tumor immunotherapies.
Lipoprotein lipase (LPL) is one of the most important factors in systemic lipid partitioning and metabolism. It mediates intravascular hydrolysis of triglycerides packed in lipoproteins such as ...chylomicrons and very-low-density lipoprotein (VLDL). Since its initial discovery in the 1940s, its biology and pathophysiological significance have been well characterized. Nonetheless, several studies in the past decade, with recent delineation of LPL crystal structure and the discovery of several new regulators such as angiopoietin-like proteins (ANGPTLs), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1 (LMF1) and Sel-1 suppressor of Lin-12-like 1 (SEL1L), have completely transformed our understanding of LPL biology.
Lipoprotein lipase (LPL) is a central player in triglyceride metabolism by catalyzing intravascular triglyceride hydrolysis. Loss-of-function Lpl causes familial chylomicronemia syndrome in humans and mice.The functional unit of LPL was thought to be a dimer, but recent studies have demonstrated that it may be a monomer.Given its pathophysiological importance in lipid partitioning, the maturation and activity of LPL is tightly controlled.In the endoplasmic reticulum (ER), the maturation and folding of nascent LPL protein requires lipase maturation factor 1 (LMF1) and Sel-1 suppressor of Lin-12-like 1 (SEL1L); and in the post-ER compartments, the activity of LPL is inhibited by angiopoietin-like protein (ANGPTL)3, 4 and 8 in a tissue-specific manner; in the endothelial lumen, LPL is associated with glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) and regulated by various apolipoproteins.
We identify sources (fossil fuel combustion versus
biomass burning) of black carbon (BC) in the atmosphere and in deposition
using a global 3-D chemical transport model GEOS-Chem. We validate the
...simulated sources against carbon isotope measurements of BC around the globe and find that the model reproduces mean biomass burning contribution
(fbb; %) in various regions within a factor of 2 (except in Europe, where fbb is underestimated by 63 %). GEOS-Chem shows that contribution from biomass burning in the Northern Hemisphere (fbb: 35±14 %) is much less than that in the Southern Hemisphere (50±11 %). The largest atmospheric fbb is in Africa (64±20 %). Comparable contributions from biomass burning and fossil fuel combustion are found in southern (S) Asia (53±10 %), southeastern (SE) Asia (53±11 %), S America (47±14 %), the S Pacific (47±7 %), Australia (53±14 %) and the Antarctic (51±2 %). fbb is relatively small in eastern Asia (40±13 %), Siberia (35±8 %), the Arctic (33±6 %), Canada (31±7 %), the US (25±4 %) and Europe (19±7 %). Both observations and model results suggest that atmospheric fbb is higher in summer (59 %–78 %, varying with sub-regions) than in winter (28 %–32 %) in the Arctic, while it is higher in winter (42 %–58 %) and lower in summer (16 %–42 %) over the Himalayan–Tibetan Plateau. The seasonal variations of Atmosphericfbb are relatively flat in North America, Europe and Asia. We conducted four experiments to investigate the uncertainties associated with biofuel emissions, hygroscopicity of BC in fresh emissions, the aging rate and size-resolved wet scavenging. We find that doubling biofuel emissions for domestic heating north of 45∘ N increases fbb values in Europe in winter by ∼30 %, reducing the discrepancy between observed and modeled atmospheric fbb from −63 % to −54 %. The remaining large negative discrepancy between model and observations suggests that the biofuel emissions are probably still underestimated at high latitudes. Increasing the fraction of thickly coated hydrophilic BC from 20 % to 70 % in fresh biomass burning plumes increases the fraction of hydrophilic BC in biomass burning plumes by 0 %–20 % (varying with seasons and regions) and thereby reduces atmospheric fbb by up to 11 %. Faster aging (4 h e-folding time versus 1.15 d e-folding time) of BC in biomass burning plumes reduces atmospheric fbb by 7 % (1 %–14 %, varying with seasons and regions), with the largest reduction in remote regions, such as the Arctic, the Antarctic and the S Pacific. Using size-resolved scavenging accelerates scavenging of BC particles in both fossil fuel and biomass burning plumes, with a faster scavenging of BC in fossil fuel plumes. Thus, atmospheric fbb increases in most regions by 1 %–14 %. Overall, atmospheric fbb is determined mainly by fbb in
emissions and, to a lesser extent, by atmospheric processes, such as aging and scavenging. This confirms the assumption that fbb in local emissions determines atmospheric fbb in previous studies, which compared measured atmospheric fbb directly with local fbb in bottom-up emission inventories.
Many‐light rendering is becoming more common and important as rendering goes into the next level of complexity. However, to calculate the illumination under many lights, state of the art algorithms ...are still far from efficient, due to the separate consideration of light sampling and BRDF sampling. To deal with the inefficiency of many‐light rendering, we present a novel light sampling method named BRDF‐oriented light sampling, which selects lights based on importance values estimated using the BRDF's contributions. Our BRDF‐oriented light sampling method works naturally with MIS, and allows us to dynamically determine the number of samples allocated for different sampling techniques. With our method, we can achieve a significantly faster convergence to the ground truth results, both perceptually and numerically, as compared to previous many‐light rendering algorithms.
Monte Carlo rendering is widely used in the movie industry. Since it is costly to produce noise‐free results directly, Monte Carlo denoising is often applied as a post‐process. Recently, deep ...learning methods have been successfully leveraged in Monte Carlo denoising. They are able to produce high quality denoised results, even with very low sample rate, e.g. 4 spp (sample per pixel). However, for difficult scene configurations, some details could be blurred in the denoised results. In this paper, we aim at preserving more details from inputs rendered with low spp. We propose a novel denoising pipeline that handles three‐scale features ‐ pixel, sample and path ‐ to preserve sharp details, uses an improved Res2Net feature extractor to reduce the network parameters and a smooth feature attention mechanism to remove low‐frequency splotches. As a result, our method achieves higher denoising quality and preserves better details than the previous methods.
Monte Carlo rendering is widely used in the movie industry. Since it is costly to produce noise‐free results directly, Monte Carlo denoising is often applied as a post‐process. Recently, deep learning methods have been successfully leveraged in Monte Carlo denoising. They are able to produce high quality denoised results, even with very low sample rate, e.g. 4 spp (sample per pixel). However, for difficult scene configurations, some details could be blurred in the denoised results. In this paper, we aim at preserving more details from inputs rendered with low spp. We propose a novel denoising pipeline that handles three‐scale features ‐ pixel, sample and path ‐ to preserve sharp details, uses an improved Res2Net feature extractor to reduce the network parameters and a smooth feature attention mechanism to remove low‐frequency splotches. As a result, our method achieves higher denoising quality and preserves better details than the previous methods.
Physically accurate rendering often calls for taking the wave nature of light into consideration. In computer graphics, this is done almost exclusively locally, i.e. on a micrometre scale where the ...diffractive phenomena arise. However, the statistical properties of light, that dictate its coherence characteristics and its capacity to give rise to wave interference effects, evolve globally: these properties change on, e.g., interaction with a surface, diffusion by participating media and simply by propagation. In this paper, we derive the first global light transport framework that is able to account for these properties of light and, therefore, is fully consistent with Maxwell's electromagnetic theory. We show that our framework is a generalization of the classical, radiometry-based light transport---prominent in computer graphics---and retains some of its attractive properties. Finally, as a proof of concept, we apply the presented framework to a few practical problems in rendering and validate against well-studied methods in optics.
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