No abstract

Understanding salt stress signaling is key to producing salt-tolerant crops. The small ubiquitin-like modifier (SUMO) is a crucial regulator of signaling proteins in eukaryotes. Attachment of SUMO onto substrates is reversible, and SUMO proteases, which specifically cleave the SUMO-substrate linkages, play a vital regulatory role during SUMOylation. We have identified two SUMO proteases, OVERLY TOLERANT TO SALT1 (OTS1) and OTS2, which are localized in the nucleus and act redundantly to regulate salt stress responses in Arabidopsis thaliana. ots1 ots2 double mutants show extreme sensitivity to salt. However, under low-salt conditions, ots1 ots2 double mutants are phenotypically similar to wild-type plants. We demonstrate that salt stress induces a dose-dependent accumulation of SUMO1/2-conjugated proteins in Arabidopsis. ots1 ots2 double mutants constitutively accumulate high levels of SUMO1/2-conjugated proteins even under nonstress conditions and show a further dramatic increase in SUMO1/2-conjugated proteins in response to salt stress. Transgenic lines overexpressing OTS1 have increased salt tolerance and a concomitant reduction in the levels of SUMOylated proteins. Conversely, the ectopic expression of the mutant ots1(C526S) protein lacking SUMO protease activity fails to produce a salt-tolerant phenotype. We show that salt directly affects OTS1-dependent signaling by inducing OTS1 protein degradation. Our results indicate a requirement for OTS1 deSUMOylation activity in plant salt tolerance responses.

Previous analysis of transcriptional changes after elicitation of Cf-9 transgenic tobacco (Nicotiana tabacum) by Avr9 peptide revealed a rapidly upregulated gene, ACRE276. We show that ACRE276 is transiently induced in wounded leaves within 15 min, but upon Avr9 elicitor treatment, this upregulation is enhanced and maintained until cell death onset in Cf-9 tobacco. ACRE276 RNA interference (RNAi) silencing in tobacco results in loss of hypersensitive response (HR) specified by Cf resistance genes. ACRE276 RNAi plants are also compromised for HR mediated by the tobacco mosaic virus defense elicitor p50. Silencing tomato (Lycopersicon esculentum) ACRE276 leads to breakdown of Cf-9-specified resistance against Cladosporium fulvum leaf mold. We confirmed that tobacco ACRE276 is an E3 ubiquitin ligase requiring an intact U-box domain. Bioinformatic analyses revealed Arabidopsis thaliana PLANT U-BOX17 (PUB17) and Brassica napus ARC1 as the closest homologs of tobacco ACRE276. Transiently expressing PUB17 in Cf-9 tobacco silenced for ACRE276 restores HR, while mutant PUB17 lacking E3 ligase activity fails to do so, demonstrating that PUB17 ligase activity is crucial for defense signaling. Arabidopsis PUB17 knockout plants are compromised in RPM1-and RPS4-mediated resistance against Pseudomonas syringae pv tomato containing avirulence genes AvrB and AvrRPS4, respectively. We identify a conserved class of U-box ARMADILLO repeat E3 ligases that are positive regulators of cell death and defense across the Solanaceae and Brassicaceae.

PURPOSE CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups. METHODS Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee. RESULTS At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel–related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report. CONCLUSION At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.