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SARS-CoV-2 continues to accumulate mutations to evade immunity, leading to breakthrough infections after vaccination. How researchers can anticipate the evolutionary trajectory of the virus in advance in the design of next-generation vaccines requires investigation. Here, we performed a comprehensive study of 11,650,487 SARS-CoV-2 sequences, which revealed that the SARS-CoV-2 spike (S) protein evolved not randomly but into directional paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance. The viral infectivity and immune resistance of variants are generally incompatible, except for limited variants such as Beta and Kappa. The Omicron variant has the highest immune resistance but showed high infectivity in only one of the tested cell lines. To provide cross-clade immunity against variants that undergo diverse evolutionary pathways, we designed a new pan-vaccine antigen (S pan ). S pan was designed by analyzing the homology of 2675 SARS-CoV-2 S protein sequences from the NCBI database before the Delta variant emerged. The refined S pan protein harbors high-frequency residues at given positions that reflect cross-clade generality in sequence evolution. Compared with a prototype wild-type (S wt ) vaccine, which, when administered to mice, induced serum with decreased neutralization activity against emerging variants, S pan vaccination of mice elicited broad immunity to a wide range of variants, including those that emerged after our design. Moreover, vaccinating mice with a heterologous S pan booster conferred complete protection against lethal infection with the Omicron variant. Our results highlight the importance and feasibility of a universal vaccine to fight against SARS-CoV-2 antigenic drift.

SARS-CoV-2 continues to accumulate mutations to evade immunity, leading to breakthrough infections after vaccination. How researchers can anticipate the evolutionary trajectory of the virus in advance in the design of next-generation vaccines requires investigation. Here, we performed a comprehensive study of 11,650,487 SARS-CoV-2 sequences, which revealed that the SARS-CoV-2 spike (S) protein evolved not randomly but into directional paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance. The viral infectivity and immune resistance of variants are generally incompatible, except for limited variants such as Beta and Kappa. The Omicron variant has the highest immune resistance but showed high infectivity in only one of the tested cell lines. To provide cross-clade immunity against variants that undergo diverse evolutionary pathways, we designed a new pan-vaccine antigen (S

All-trans retinoic acid (ATRA) has demonstrated notable success in the treatment of acute promyelocytic leukemia (APL) by inducing granulocytic differentiation. The underlying mechanisms of ATRA therapeutic effects have not been entirely clarified. Here, we reported that the regulation of neddylation, a ubiquitination-like post-translational modification, was involved in the treatment of ATRA on APL. Treating APL cells with ATRA led to the degradation of UBA3, a subunit of neddylation E1. Lysosome-autophagy pathway but not proteasome pathway was responsible for the degradation of UBA3. Neddylation suppression in APL cells was capable of inducing apoptosis, differentiation and proliferation inhibition, suggesting a pivotal role of neddylation in APL cells. ATRA treatment also led to UBA3 degradation in primary APL cells. Taken together, our findings indicated that neddylation was important to maintain the malignant features of APL cells, and suppression of neddylation was involved in the effects of ATRA on APL cells.

Autophagy plays a central role in maintaining T cell homeostasis. Our previous study has shown that hepatocyte-specific deficiency of receptor for activated C kinase 1 (RACK1) leads to lipid accumulation in the liver, accompanied by impaired autophagy, but its in vivo role in T cells remains unclear. Here, we report that mice with T cell-specific deletion of RACK1 exhibit normal intrathymic development of conventional T cells and regulatory T (Treg) cells but reduced numbers of peripheral CD4+ and CD8+ T cells. Such defects are cell intrinsic with impaired mitochondrial clearance, increased sensitivity to cell death, and decreased proliferation that could be explained by impaired autophagy. Furthermore, RACK1 is essential for invariant natural T cell development. In vivo, T cell-specific loss of RACK1 dampens concanavalin A-induced acute liver injury. Our data suggest that RACK1 is a key regulator of T cell homeostasis.

Neddylation is a ubiquitination-like pathway. It has been reported that neddylation inhibition with the pharmacological agent MLN4924 potently uppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, by preventing the degradation of phosphorylated inhibitor of κB (p-IκB) in macrophages. However, whether neddylation serves a similar role in neutrophils remains unknown. In the present study MLN4924 treatment led to the accumulation of P-IκBα in neutrophils as well as the decreased production of TNF-α, IL-6 and IL-1β in response to LPS, in a dose-dependent manner. The viability of neutrophils was only marginally affected in the same conditions, without statistical significance. Furthermore, the nuclear factor (NF)-κB inhibitor JSH-23 mimicked the effects of MLN4924 in neutrophils, and the inhibitory effects of MLN4924 on LPS-induced proinflammatory cytokine production diminished in the presence of JSH-23. Thus, the results of the present study suggest that neddylation inhibition suppresses neutrophil function by suppressing the NF-κB signaling pathway.

SummaryAutophagy is essential for maintaining tissue homeostasis. Although adaptors have been demonstrated to facilitate the assembly of the Atg14L-Beclin 1-Vps34-Vps15 complex, which functions in autophagosome formation, it remains unknown whether the autophagy machinery actively recruits such adaptors. WD40-repeat proteins are a large, highly conserved family of adaptors implicated in various cellular activities. However, the role of WD40-repeat-only proteins, such as RACK1, in postnatal mammalian physiology remains unknown. Here, we report that hepatocyte-specific RACK1 deficiency leads to lipid accumulation in the liver, accompanied by impaired Atg14L-linked Vps34 activity and autophagy. Further exploration indicates that RACK1 participates in the formation of autophagosome biogenesis complex upon its phosphorylation by AMPK at Thr50. Thr50 phosphorylation of RACK1 enhances its direct binding to Vps15, Atg14L, and Beclin 1, thereby promoting the assembly of the autophagy-initiation complex. These observations provide insight into autophagy induction and establish a pivotal role for RACK1 in postnatal mammalian physiology.