Splenomegaly, a major symptom in Plasmodium infection, is extensively studied for its immunopathological role in mice malaria model infected with Plasmodium berghei ANKA. The status of autophagic regulation in hosts in malaria pathogenesis remains unreported till date. This study demonstrated the autophagy, proteasomal degradation and NRF2-KEAP1 antioxidant pathway status in the host during Plasmodium infection taking murine spleen as our organ of interest. Initial staining and autophagic gene expression indicate a possibility of autophagic pathway activation. Although the conversion of LC3A to LC3B and lysosome-autophagosome fusion increases, the final degradation step remains incomplete. Resultant upregulation of p62 and its altered phosphorylated status enhances its binding to keap1 causing NRF2 translocation to the nucleus. NRF2 act as transcription factor upregulating p62 level itself leading to an autoinduction loop of p62 expression. Interestingly, enhancement of P62 interaction with proteasome subunit RPT1 indicates a possible role in transporting ubiquitinated cargo to proteasome complex. Ubiquitination level increased with subsequent upregulation of all three modes of proteasomal degradation i.e trypsin-like, caspase-like and especially chymotrypsin-like. Sqstm1/p62 plays a critical central role in regulating autophagy, proteasomal degradation, and NRF2-KEAP1 pathway. The incomplete autophagic flux in the final step may be a key therapeutic target, as autophagic degradation and subsequent pathogenic peptide presentation is of utmost necessity for downstream immune response.

脾肿大是疟原虫感染的主要症状，由于其在感染了伯氏疟原虫ANKA的小鼠疟疾模型中的免疫病理作用而被广泛研究。到目前为止，疟疾发病机理中宿主自噬调节的状态尚未报道。这项研究表明，在疟原虫期间，宿主体内的自噬，蛋白酶体降解和NRF2-KEAP1抗氧化途径状态以鼠脾为我们感兴趣的器官的感染。初始染色和自噬基因表达表明自噬途径被激活的可能性。尽管LC3A向LC3B的转化和溶酶体-自噬体融合增加，但最终降解步骤仍不完全。结果是p62的上调及其磷酸化状态的改变增强了其与keap1的结合，从而导致NRF2易位至细胞核。NRF2本身作为转录因子上调p62水平，导致p62表达的自诱导环路。有趣的是，P62与蛋白酶体亚基RPT1相互作用的增强表明在将泛素化的货物运输到蛋白酶体复合物中可能发挥作用。泛素化水平随着蛋白酶体降解的所有三种模式（即胰蛋白酶样，caspase样，尤其是胰凝乳蛋白酶样。Sqstm1 / p62在调节自噬，蛋白酶体降解和NRF2-KEAP1途径中起着关键的核心作用。最终步骤中不完全的自噬通量可能是关键的治疗靶标，因为自噬降解和随后的致病性肽呈递对于下游免疫反应至关重要。