Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, TX 77021, USA.
The Department of Biomedical Engineering, Texas A&M University, Houston, TX 77030, USA.
Cells. 2024 Aug 26;13(17):1431. doi: 10.3390/cells13171431.
TRIM44, a tripartite motif (TRIM) family member, is pivotal in linking the ubiquitin-proteasome system (UPS) to autophagy in multiple myeloma (MM). However, its prognostic impact and therapeutic potential remain underexplored. Here, we report that TRIM44 overexpression is associated with poor prognosis in a Multiple Myeloma Research Foundation (MMRF) cohort of 858 patients, persisting across primary and recurrent MM cases. TRIM44 expression notably increases in advanced MM stages, indicating its potential role in disease progression. Single-cell RNA sequencing across MM stages showed significant TRIM44 upregulation in smoldering MM (SMM) and MM compared to normal bone marrow, especially in patients with t(4;14) cytogenetic abnormalities. This analysis further identified high TRIM44 expression as predictive of lower responsiveness to proteasome inhibitor (PI) treatments, underscoring its critical function in the unfolded protein response (UPR) in TRIM44-high MM cells. Our findings also demonstrate that TRIM44 facilitates SQSTM1 oligomerization under oxidative stress, essential for its phosphorylation and subsequent autophagic degradation. This process supports the survival of PI-resistant MM cells by activating the NRF2 pathway, which is crucial for oxidative stress response and, potentially, other chemotherapy-induced stressors. Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress. Collectively, our discoveries highlight TRIM44's significant role in MM progression and resistance to therapy, suggesting its potential value as a therapeutic target.
TRIM44 是一个三联基序（TRIM）家族成员，在多发性骨髓瘤（MM）中将泛素-蛋白酶体系统（UPS）与自噬连接起来至关重要。然而，其预后影响和治疗潜力仍未得到充分探索。在这里，我们报告称，在多发性骨髓瘤研究基金会（MMRF）的 858 名患者队列中，TRIM44 的过表达与不良预后相关，这一结果在原发性和复发性 MM 病例中均存在。TRIM44 的表达在晚期 MM 阶段显著增加，表明其在疾病进展中可能发挥作用。跨越 MM 阶段的单细胞 RNA 测序显示，在冒烟型 MM（SMM）和 MM 中与正常骨髓相比，TRIM44 的表达显著上调，特别是在具有 t（4；14）细胞遗传学异常的患者中。这项分析还进一步表明，高 TRIM44 表达预测对蛋白酶体抑制剂（PI）治疗的反应性降低，突出了其在 TRIM44 高 MM 细胞中的未折叠蛋白反应（UPR）中的关键功能。我们的研究结果还表明，TRIM44 在氧化应激下促进 SQSTM1 寡聚化，这对其磷酸化和随后的自噬降解至关重要。这个过程通过激活 NRF2 通路来支持 PI 耐药 MM 细胞的存活，该通路对于氧化应激反应以及潜在的其他化疗诱导的应激至关重要。此外，TRIM44 抵消了 TRIM21 介导的抗氧化反应抑制，增强了 MM 细胞在氧化应激下的存活。总之，我们的发现强调了 TRIM44 在 MM 进展和对治疗的耐药性中的重要作用，表明其作为治疗靶点的潜在价值。
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